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Emedgene

Get Started with Emedgene

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Emedgene analyze manual

Getting around the platform

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Managing data storage

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Cases tab

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Creating a single case

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Creating multiple cases

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Reviewing a case

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Variant page

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Variant visualization setup

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Settings

Click on the user initials or profile picture at the rightmost corner of the Top navigation panel to open the Settings dropdown menu. From there, you can enter:

Note: Organization settings are accessible only for users having a Manager role.

Next to the user's initials or profile picture is a question mark Help icon. Clicking on this icon expands a dropdown menu with the following options:

  • What's New: check out the new features, enhancements, or any other updates related to the platform.

  • Coming soon: Walkthroughs & Feature Requests

Caution: Please be aware that when performing a task, such as uploading a new sample, clicking on the buttons in the Top navigation panel may terminate the progress. However, for the most part, changes and annotations made on the analysis pages are auto-saved.

Add or edit your professional credentials, profile picture, contact information and organization's details, and review and permissions granted to you.

, custom , , create, edit and delete , set how long until a case becomes "stale", and assign user groups.

Add, activate and inactivate users and manage .

networks, for each network, and networks.

for your organization, , and (the latter - only for ILMN cloud users).

Help Center: Access the user manual and learn how to leverage powerful features to serve your patients or advance your research;

My Settings
roles
Management
Manage data storage
Case statuses
Case labels
gene lists
User Management
user roles
Network
Create
establish data sharing policies
delete
leave
Organization Settings
(33.0+)
Choose a software version
set up a case identifier
select your preferred URLs
Help
NextUser roles

How can Emedgene help you solve a case?

Emedgene is an AI-based platform, incorporating machine learning throughout the analysis and interpretation workflow in order to deliver the fastest time from genomic data to decisions. We apply machine learning models that retrieve evidence-backed answers and provide exceptional decision support.

  • The platform is not a black box, and overlays a layer of explainable AI (XAI), presenting supporting evidence from the literature and databases which significantly reduces the time to interpret a case.

  • The algorithms use a proprietary Emedgene knowledge graph which incorporates information extracted from literature with Natural Language Processing, as well as from public databases and is updated on a monthly basis.

  • Dozens of additional algorithms are incorporated throughout the workflow.

Overall, the system combines AI in a highly optimized and customizable workbench, in order to automate the most time-intensive aspects of genomic analysis and research.

Emedgene’s automated interpretation algorithms generate an accurate shortlist of up to 10 potential causative variants. In a joint study of 180 solved cases with Baylor Genetics, 96% of cases were successfully solved by the algorithm. See Meng et al, , 2023 publication for more details.

Genetics in Medicine

Dashboard

The Dashboard provides a glance at key performance indicators for an organization and depicts an overview of the user activity on the Emedgene platform.

This page is divided into two panels and contains the following subsections:

Lefthand panel

  • Emedgene Knowledge Base panel reveals the total amount of known polymorphisms, pathogenic variants, and gene-disease connections considered during analysis. It also indicates the number of scholarly publications processed by Emedgene's novel textual recognition platform, backed by natural-language processing and artificial intelligence.

  • Diagnostic Yield panel presents the proportion of "solved" cases out of the total number of the organization's cases of the same type.

  • Status Diagram panel displays the total number of the organization's submitted cases as well as the numbers of cases under each status.

  • Stale Cases panel highlights the cases that are stuck at one of the intermediate stages of the analysis, and are not finalized.

Righthand panel

Get started with Emedgene

Welcome to Emedgene, where we unlock genomic insights for hereditary disease and streamline your tertiary analysis workflows.

So you've signed in and can't wait to get started? Here we will guide you through the platform architecture, case creation, and results review. You can dive a bit deeper by following the links and exploring manuals for the platform's applications:

Look around

By clicking on the corresponding buttons, you can enter:

Create a case

  • Select file type,

  • Upload files,

  • Create a family tree,

  • Annotate each sample with clinical information,

  • Specify analysis details, and

  • Launch the analysis!

You'll be notified when results are ready.

Examine the analysis results

Network Activities: The right panel displays a timeline of activities performed by multiple users within the organization. This log includes activity like creating a case, verifying a Preset, changing a , generating a report, etc.

- Genomic analysis workbench, where you can accession, interpret, curate and report on your cases, while also efficiently managing the lab workflow.

- A repository for all of your organizational curated knowledge.

The platform is operated from the .

page

page

menu

dropdown menu

dropdown menu

To enter the flow, click on the namesake button on the . Here:

Select a case to review on the page. You'll be directed to the that:

Showcases an AI-curated suggested to be checked first, namely and ,

Provides numerous customizable to help you by yourself, and

Documents all the case-related information like , , and used during case analysis.

On the , each variant can be thoroughly investigated and accordingly .

When you're ready to , indicate the end result of the analysis and variants to be reported in the Case interpretation widget.

Case status
Analyze
Curate
Top navigation panel
Cases
Add new case
Emedgene Applications
Help
Settings
Add new case
Top navigation panel
Cases
Individual case page
shortlist of variants
Most Likely Candidates
Candidates
filters
explore the total list of genetic variants
Case status
sample quality metrics
versions of all the resources
Variant page
tagged
finalize the case

Okta identity management

The Emedgene platform utilizes the Okta Identity Management solution to control user access. This improves user management, enhances access and authentication security, and allows organizations to implement single sign-on for their users.

​

User roles

The available roles for Emedgene are described below:

User Role
Description
Component / Flow
User Level

Acmg Tags

Allows to see ACMG Tags

Analyze > Variant page

All

Acmg Tags Edit

Allows to edit ACMG classification

Analyze > Variant page

Analyst, Director, Manager

Add New Test

Allows to manually create a case or (32.0+) upload a batch of cases via .csv

Analyze > Add a new case

Analyst, Director, Manager

Apidocs

Allows to see API documentation

Analyze

IT team

Auto Analysis

Allows to see the AI Shortlist analysis results

Analyze > Variant page

All

Candidate Compound With

Allows to combine two compound variants by gene name on the candidate page

Analyze > Case page

Analyst, Director, Manager

Change Finalized Test Status

Allows to unlock a finalized case

Analyze > Case page

Director, Manager

Check Preset

Allows to implement Presets from a list

Analyze > Case page

Analyst, Director, Manager

Comment

Allows to send a comment

Analyze > Case page

Analyst, Director, Manager

Comment Delete

Allows to delete a comment

Analyze > Case page

Manager

Create Report

Allows to generate report template

Analyze > Clinical report

Director, Manager

Create Variant

Allows to create an additional variant

Analyze > Case page

Director, Manager

Developer

Allows to see developer settings (Webhook)

Analyze

IT team

Download

Allows to download files

Analyze > Case page

Analyst, Director, Manager

Due Date

Allows to edit due date

Analyze > Case page

Analyst, Director, Manager

Edit Test

Allows to edit test's info

Analyze > Case page

Analyst, Director, Manager

Evidence

Allows to see evidence page

Analyze > Variant page

All

Evidence Edit

Allows to edit evidence page

Analyze > Variant page

Analyst, Director, Manager

Evidence Generate

Allows to generate initial evidence

Analyze > Variant page

Analyst, Director, Manager

Evidence Pathogenicity Edit

Allows to edit evidence pathogenicity

Analyze > Variant page

Analyst, Director, Manager

Evidence Text Edit

Allows to edit evidence text (Variant interpretation)

Analyze > Variant page

Analyst, Director, Manager

Gene Lists Read Only

Allows to show the gene list

Analyze

All

Gnomad Genome

Allows to see GnomAD genome data annotation

Analyze > Variant page

All

KMS

Allows to access Emedgene Curate

Curate

All

KMS Create Gene

Allows user to create a new gene in KMS

Curate

Manager

KMS Create Variant

Allows to create new variant in KMS

Curate

Manager

KMS Export

Allows user to export from varpage to the KMS

Curate

All

KMS Import Network Variant

Allows user to import variants from Network to Curate

Curate

Manager

KMS Update Disease ID

Allows to update disease ID of the variant in KMS

Curate

Manager

KMS Update Gene Interpretation

Allows user to update gene interpretation in KMS

Curate

Manager

KMS Update Gene Transcript Ref Sequence

Allows user to update a gene selected transcript in KMS

Curate

Manager

KMS Update Gene Note

Allows user to update gene note in KMS

Curate

Manager

KMS Update Interpretation

Allows to update interpretation of the variant in KMS

Curate

Manager

KMS Update Note

Allows to update variant note in KMS

Curate

Manager

KMS Update Pathogenicity

Allows to update pathogenicity of the variant in KMS

Curate

Manager

KMS Update Transcript

Allows to update transcript of the variant in KMS

Curate

Manager

Load Bam IGV

Allows to synchronize external IGV viewer with the platform

Analyze > Case page

All

Manage Case Default Page (34.0+)

Allows to set a default page upon entering a case

Analyze > Settings

Manager

Manage Case Identifier (33.0+)

Allows to set a custom case identifier

Analyze > Settings

Manager

Manage Column Order (34.0+)

Allows to customize the default order of Variant table columns.

Analyze > Settings

Manager

Manager Edit Variant Tags

Allows user to manage variant tags

Analyze > Settings

Director, Manager

Manage Gene List

Allows to create, edit gene lists

Analyze > Settings

Manager

Manage Gene List Visibility

Allows to manage gene list visibility

Analyze > Settings

Manager

Manage Kit Bed (30.0+)

Allows user to manage kits and bed uploads

Analyze > Settings

Manager

Manage Labels

Allows to manage labels

Analyze > Settings

Manager

Manage Platform Version (33.0+)

Allows to set a platform version

Analyze > Settings

Manager

Manage S3 Credentials (32.0+)

Allows to create access key and secret key; deactivate, activate and delete access key.

Analyze > Settings

Manager

Manager Support Access (31.0+)

Enable/disable support access to the organization

Analyze > Settings

Manager

Manage Test Presets

Allows to create Presets from gene lists, filter

Analyze > Settings

Analyst, Director, Manager

Manage URL Pattern (33.0+)

Allows to set a platform version

Analyze > Settings

Manager

Manager

Organizational admin (manager) role

Analyze

Manager

Multiple Storage

Allows to change the organization URL pattern

Analyze > Settings

Manager

Network

Allows to see available networks, request to join networks, leave networks, approve or reject invitations to join networks, edit existing networks of organization

Analyze > Settings

Manager

Network Create

Allows to create a new network

Analyze > Settings

Manager

Network Manage (32.0+)

Allows to create a network and define its sharing policy; leave networks

Analyze > Settings

Manager

Phenomatcher

Allows to filter by phenotypic match

Analyze > Case page

All

Preset Create (34.0+)

Allows to create Presets from active filters

Analyze > Case page;

Analyze > Settings

Analyst, Director, Manager

Preset Group Create (34.0+)

Allows to create and edit Preset groups

Analyze > Settings

Analyst, Director, Manager

Preset Group Default (34.0+)

Allows to set a default Preset group

Analyze > Settings

Manager

Preset Group Download (34.0+)

Allows to download a legacy (V1) Preset group JSON file

Analyze > Settings

Manager

Preset Group Hide (34.0+)

Allows to hide a Preset group from the Preset groups list offered at case creation

Analyze > Settings

Analyst, Director, Manager

Preset Group Revert (34.0+)

Allows to revert migration of a legacy Preset group

Analyze > Settings

Manager

Preset Delete (34.0+)

Allows to delete a non-locked Preset

Analyze > Settings

Analyst, Director, Manager

Preset Lock (34.0+)

Allows to lock and unlock editing the Preset

Analyze > Settings

Manager

Preset Manage (34.0+)

Allows to view and edit a Preset in JSON format

Analyze > Settings

Manager

Re Upload Tab

Allows to re-upload files

Analyze > Case page

Analyst, Director, Manager

Render Template

Allows to create a variant interpretation paragraph on the fly

Analyze > Clinical report

Analyst, Director, Manager

Report

Allows to export a report as a PDF

Analyze > Clinical report

Director, Manager

Report Preview

Allows to preview report

Analyze > Clinical report

All

Sanger Edit

Allows to edit Sanger sequencing information

Analyze > Variant page

Analyst, Director, Manager

Storage Provider

Allows to manage storage providers

Analyze > Settings

Manager, IT team

Tag Variant

Allows to tag a variant

Analyze > Variant page

Analyst, Director, Manager

Test Status

Allows to change test status

Analyze > Case page

Analyst, Director, Manager

Test Status Move to Trash

Allows to assign a Move to trash Case status

Analyze > Case page

Manager

Test Status to Finalized

Allows to change case status to finalized

Analyze > Case page

Director, Manager

Transcript Edit

Allows to change the default transcript for variants

Analyze > Variant page

Analyst, Director, Manager

Unknown Phenomatch

Allows to use Unknown Phenomatch variant filter

Analyze > Case page

All

Upload

Allows to upload files to be associated to a case

Analyze > Add a new case

Analyst, Director, Manager

User

Regular user role

Analyze

All

User Management

Allows to manage users

Analyze > Settings

Manager

User Read (30.0+)

Allows users access to organization data

Analyze

All

User Rerun Case

Allows to rerun cases

Analyze > Edit case info

Analyst, Director, Manager

Versions Tab

Allows seeing the versions tab

Analyze > Case page

All

Help

Click on the question mark icon of the Top navigation panel to open the Help dropdown menu.

From there, you can access:

  • Help Center. Feeling curious? Dive right in.

  • What's New. Check out the release notes to be on top of our latest and greatest features!

Manage data storages

To directly import files from your storage, link storage to your organization in Emedgene.

How to create a link between storage and organization:

  1. Select the Management tab. Under Storage is a list of currently linked storages. To add a new one press on Add Storage button.

  1. Choose a Storage Type from:

    1. Azure Data Lake;

    2. Azure Blob;

    3. AWS S3;

    4. File Transport Protocol (FTP);

    5. Secure File Transport Protocol (SFTP);

    6. Illumina Basespace (BSSH);

    7. Illumina Connected Analytics (ICA).

  1. Fill in the required credentials.

  2. Click on Add storage:

  1. Check the connection to confirm that the storage is successfully linked.

To do this, find the storage in the Storage List and check the cloud icon next to its name: 1. If it's green, the connection is set correctly; 2. If it's red and strikethrough, something went wrong. Hover over the icon to see details.

How to edit storage information:

In the Storage List press Manage on the right to the storage details.

How to remove a link to storage:

In the Storage List press Delete on the right to the storage details.


Emedgene users are defined by roles. Roles are managed in > . Access to the User Management tab is restricted to those with the appropriate permission.

If you are not seeing part of the roles from the user management interface, please be in touch with our .

Note: to have access to data storage management, you must have Manager and Multiple Storage .

Click on the user initials or profile picture at the rightmost corner of the Top navigation panel to open the dropdown menu. Select Settings.

If data is deleted or moved from the customer's storage, it might adversely affect the case. To learn more about possible consequences, check out this table:

Settings
User Management
support
https://github.com/illumina-swi/emedgene-docs/blob/prod/docs/emedgene-analyze-manual/managing_data_storage/bring-your-own-bucket.md#managing-aws-s3-lifecycle-policy
user roles
Settings

Manage S3 credentials

Whenever an organization is created, we automatically allocate bucket folders in AWS S3 cloud storage to it:

  • Path for upload

Folder intended to store input case files.

Authorized user has view and upload privileges.

  • Path for download (32.0+)

This folder contains a partially annotated (excluding results of proprietary algorithms) VCF file per case.

Authorized user has view and download privileges.

  • Path for DRAGEN output (32.0+)

This folder contains DRAGEN output files.

Authorized user has view and download privileges.

You can create and use up to two dynamic access keys at the same time.

When you require technical support, you have the option to generate a new key pair specifically for the troubleshooting process. After the issue has been resolved, you can delete the credentials to ensure security of your system.

The newly generated credentials will only be saved in AWS Identity and Access Management (IAM) and not in our database.

How to create a key pair

  1. In Settings > Management > S3 Credentials, click on Create Access Key.

  2. You can retrieve the secret access key only when you initially create the key pair. If you lose it, you have to create a new key pair. To immediately copy the secret access key to a secure location, use the Copy to clipboard button.

How to deactivate a key pair

In Settings > Management > S3 Credentials, click on Deactivate in the corresponding key pair card.

How to activate an inactive key pair

In Settings > Management > S3 Credentials, click on Activate in the corresponding key pair card.

How to delete a key pair

In Settings > Management > S3 Credentials, click on Delete in the corresponding key pair card. Only inactive key pairs can be deleted.

Top navigation panel

The Top navigation panel of the platform serves as a guide to the platform. It contains:

  • Case search bar

As of version 2.26:

To get access to your upload, download and DRAGEN output folders, you need to get a key pair consisting of an access key ID and a secret access key. , , and credentials is available for users with Manager and Manage S3 Credentials .

, and buttons lead to the corresponding pages

dropdown menu activated by clicking on the user name or profile picture

dropdown menu activated by clicking on the question mark icon

activated by clicking on the app launcher icon on the left

<Region_Cloud>-emg-auto-samples/<org_name>/upload/
<Region_Cloud>-emg-downloads/<org_name>/ 
<Region_Cloud>-emg-auto-results/<org_name>/ 
Dashboard
Cases
Add new case
Settings
Help
Emedgene Applications menu
roles
Creating
deactivating
activating
deleting

Manage BaseSpace storage

Log in to Emedgene and navigate to Settings in the upper right-hand corner of the page.

Click on the Management tab and then on Add Storage.

Choose Illumina BaseSpace storage type.

Fill Client Key, Client Secret and App Token as provided from BaseSpace (a description on how to get this information is provided below) and click Add storage to complete the setup.

Via Command Line

Prerequisite

Install BaseSpace CLI (Command Line Interface)

# Linux
$ wget "https://launch.basespace.illumina.com/CLI/latest/amd64-linux/bs" -O $HOME/bin/bs
# Mac
$ wget "https://launch.basespace.illumina.com/CLI/latest/amd64-osx/bs" -O $HOME/bin/bs
# or
$ brew tap basespace/basespace && brew install bs-cli
# Windows
$ wget "https://launch.basespace.illumina.com/CLI/latest/amd64-windows/bs.exe" -O bs.exe

Authenticate

On BSSH, login to the workgroup you want to connect as the storage.

Once the BaseSpace CLI is installed, run the authentication command in the terminal.

$ bs auth

The command will direct you to a link which requires to login.

After the authentication was completed successfully, find the access token in the config file.

$ cat .basespace/default.cfg

The result should look like -

apiServer   = https://api.basespace.illumina.com
accessToken = 

Populate the App_token with the accessToken value, and Server with the apiServer URL from the BSSH config file.

Client_key will be displayed in subsequent menus, so a descriptive name such as the workgroup name can be used.

Client_secret is unused when the App_token is available and can be set to "x".

Via BaseSpace Developer Portal

Go to My Apps and click Create a new Application.

Fill details for the application and click on create an application.

Fill details and press save.

You will need to fill all the fields that it requested, please add “NA” to them.

Go to My Apps and click on your new app. Then go to the credentials tab.

You will find the Client ID (Client Key), Client Secret and App Token to enter to Emedgene platform.\

Adding BSSH account to your Emedgene account

  1. Log in into the desired Emedgene organization.

  2. Go to Settings

  3. Go to Management tab

  4. Click on Add Storage

  5. Select BaseSpace:

  1. Add the information from your “Credentials” of the App previously created in BSSH.

Emedgene Applications menu

The Emedgene platform is divided into two applications:

  • Analyze - genomic analysis workbench,

  • Curate - the knowledge management system.

To switch from Analyze to Curate:

To switch from Curate to Analyze:

Go to the nine-dot app launcher icon located on the Curate navigation panel and select Analyze from the dropdown menu.

Bring Your Own Bucket

Case Type
File Type
Expected effect

FASTQ

FASTQ/BAM/CRAM (input)

Reanalysis will fail (will be fixed)

FASTQ

CRAM (Output)

Reanalysis will fail

FASTQ

VCFs

Reanalysis will fail

FASTQ

CSV, etc

Reanalysis will fail

VCF

BAM/CRAM (visualizations)

Visualization will fail

VCF

VCF (input)

Reanalysis will fail

VCF

CSV, etc

Reanalysis will fail (will be fixed)

This feature is only related to saving Dragen output files in your own bucket when using Dragen through Emedgene (without ICA).

If you are looking to:

  • Import data from AWS S3 to Emedgene go to Manage data storages

  • Integrating any data storage to Emedgene go to Manage data storages

  • Download any data from Emedgene go to Manage S3 credentials


Bring your own bucket is only available for Enterprise level support accounts and require Illumina support for setup


Bring Your Own Bucket

Bring Your Own Bucket, also known as BYOK, enables you to control your DRAGEN file outputs.

However, if you have an Enterprise account and you would like Emedgene managed dragen solution to save the DRAGEN output files in your own bucket, reach out to techsupport@illumina.com and follow this steps:

1. Create an AWS bucket

Emedgene requires access to the root folder, which means a dedicated bucket might be appropriated.

2. Edit Bucket policy

Bucket policy should allow Emedgene user access to the bucket.

Example bucket policy:

{
    Coming Soon
}

3. Allow illumina.com and emedgene.com for CORS

Example CORS policy:

{
    Coming Soon
}

4. Test and validate the configuration with Illumina support

We will require to run a case and validate the managed DRAGEN pipeline finish successfully and all features are available in the platform.

The BYOB solution means you managed your own data, meaning if you accidentally deleted or moved the data the integration with Emedgene might break. You are responsible for your DRP and data backup solutions.


Managing AWS S3 Lifecycle policy

If a customer enables an AWS S3 Lifecycle policy in order to archive or change the S3 tiers for different files, they might create an adverse effect on the platform.

Case Type
File Type
Expected effect

FASTQ

FASTQ/BAM/CRAM (input)

Reanalysis will fail (will be fixed)

FASTQ

CRAM (Output)

Reanalysis will fail

FASTQ

VCFs

Reanalysis will fail

FASTQ

CSV, etc

Reanalysis will fail

VCF

BAM/CRAM (visualizations)

Visualization will fail

VCF

VCF (input)

Reanalysis will fail

VCF

CSV, etc

Reanalysis will fail

(will be fixed)

Manage GCS storage (V37.0+)

Coming in V37.0: Google Cloud storage support

Google Cloud Storage Credentials update procedure

How to get the client credentials?

  1. Go to the google cloud Console.

  2. Navigate to IAM & Admin - In the left sidebar, go to IAM & Admin > Service Accounts.

  1. Create a New Service Account: Click on the "Create Service Account" button at the top.

  1. Fill in the Service Account Details:

    • Service account name: Give your service account a name.

    • Service account ID: This will be automatically generated based on the name.

    • Description: Optionally, provide a description for the service account.

    Click "Create and Continue".

    example:

  1. Assign Roles to the Service Account:

    • In the Grant this service account access to project step, you’ll assign the necessary roles.

    • Grant these role:

      • "storage object viewer" (read-only access)

  2. Create the Service Account:

    • After assigning the roles, click "Done".

  3. Generate and Download a Key:

    • Find your newly created service account, click the three dots on the right, and select "Manage Keys".

    • Click Add Key > Create New Key and choose the JSON format.

    • Download the key and store it securely, as it is used for authentication in your code or applications.

  4. Encode the key in base 64:

    • use python function: put this function and your json (here named json_file.json) in the same directory and run.\

      import json
      import base64
      
      
      def encode_json_to_base64(json_file):
          # Read JSON data from file
          with open(json_file, 'r') as file:
              json_data = json.load(file)
      
          # Convert the JSON data to a string
          json_str = json.dumps(json_data)
      
          # Encode the string to bytes, then to Base64
          json_bytes = json_str.encode('utf-8')
          base64_bytes = base64.b64encode(json_bytes)
      
          # Convert Base64 bytes back to a string
          base64_str = base64_bytes.decode('utf-8')
          # Print the Base64-encoded string
          print(base64_str)
      
      
      encode_json_to_base64('json_file.json')
    • save the output printed.

Add the storage provider to Emedgene platform:

  • Add the above 3 values into the appropriate fields:

    • Client_credentials_base64: pasting the output of 8.

    • Bucket: the bucket name.

    • Path: for default, fill with / else, put your path in the bucket. Seperate directories with /

CORS - Visualisation

  1. Select Your Platform (Windows, macOS, or Linux), download and run.

  2. Initialize and Authenticate with Google Cloud: In the Cloud SDK Shell/terminal, run: gcloud init This will open a browser window to authenticate your Google account. Follow the instructions to log in and select your project.

  3. Set CORS Configuration via gcloud: Create a JSON file (cors.json) on your machine with the CORS rules. Example\ it should look like:

    [
        {
          "origin": ["https://<host_name>.emg.illumina.com"],
          "method": ["GET"],
          "responseHeader": ["emgauthorization"],
          "maxAgeSeconds": 3600
        }
    ]

notice:

  • origin: if using Illumina cloud:

    https://host_name.emg.illumina.com

    else, Emedgene cloud:

    https://host_name.emedgene.com

  1. Apply CORS Configuration to Your Bucket: run the next command. gcloud storage buckets update gs://your-bucket-name --cors-file=cors.json

  2. Verify the CORS Configuration: gcloud storage buckets describe gs://your-bucket-name

Bring Your Own Key

Bring your own key is only available for Enterprise level support accounts and require Illumina support for setup

Scope

Bring Your Own Key (BYOK) is a security feature that allows clients to use their own encryption keys to protect their data. This ensures that clients maintain control over their encryption keys and, consequently, their data. Only Enterprise level support accounts can access this feature, and it requires assistance from Illumina support for setup.

Supported Key Management Services

Illumina supports integration with popular Key Management Services (KMS) such as Azure Key Vault and AWS KMS for managing your encryption keys. This integration allows clients to use their existing key management solutions for generating, storing, and managing their keys securely.

Azure Key Vault

AWS KMS

These integrations ensure robust key management capabilities and enhance the security of your data through a combination of Illumina's BYOK feature and your preferred KMS provider.

Risk of Losing a Key

Losing the encryption key means that all data encrypted with that key will be inaccessible. This can lead to permanent loss of access to crucial information. It is imperative that clients securely store and manage their keys to prevent such risks.


Setup

Azure Key Vault Setup

Emedgene’s API server will encrypt the client’s information before storing in Emedgene’s database and decrypt that information when needed (e.g. running the pipeline). The key vault is managed by the customer. The customer needs to provide the following information.

Please see below instructions on how to get or create it

Application Tokens:

  • Client Id

  • Client Secret

  • Tenant Id

The key information:

  • Key URL

Create a new Application

  1. Navigate to App registration

  2. Register a new application, click “Register”

  3. When you created the app, please copy Application (client) ID and Directory (tenant) ID

  4. Go to Certificates and secrets (in the left menu)

  5. Press “New client secret” and provide the “Value”

Please note the expiration date of the secret, as once expired it will impair our system.

Create a new Key

  1. Press New Key (Create key vault)

  2. Specify key vault name, region (ie. East US) and pricing tier

  3. Click “Next” to Access Policies

  4. Press “Add access policy” and set Key permissions:

    1. Key Management Operations: -

    2. Cryptographic Operations: Decrypt, Encrypt, Unwrap Key, Wrap Key

  5. Then set Secret permissions:

    1. Secret Permission: Get

    2. Select principal: select the application you created before (in Create a new Application step)

  6. Finish with “Review + create”

Find key details

  1. Navigate to the newly created Key vault

  2. Select keys on the left side, select the key

  3. Select the current version and copy “Key Identifier” https://<key-vault-name>.vault.azure.net/keys/<key-name>/<key-version>\

AWS Key Management Service (KMS) Setup

Description is coming soon.

Please reach out to tech-support@illumina.com to get help with this setup.


Architecture

Emedgene’s API server will encrypt the client’s information before storing in Emedgene’s database and decrypt that information when needed (e.g. running the pipeline). The key vault is managed by the client, and Emedgene will only be provided with access to encrypt/decrypt functions in that key vault. This guarantees that the clients controls access to the information.

Illustration of data flow when creating a case in Emedgene platform:

Illustration of data flow when reading a case data from Emedgene platform:

A preliminary step to this solution is having a key vault owned by the client, and a key that Emedgene is given access to.

The client will create an access policy in the key vault of type “Application” and provide the matching key and secret to Emedgene. The access policy must contain permissions to perform encrypt and decrypt actions.

In order for Emedgene to integrate with the key, depending on the key vault provider, the client needs to provide the following information:

  • Client Id

  • Client Secret

  • Tenant Id

  • Key vault name

  • Key name

Searching Encrypted Fields

Since some of our platform search capabilities run directly on the DB, we can’t directly search any data that is encrypted. To overcome this, we will implement a hashing search functionality as follows.

  • The case data will still be fully encrypted in the DB as it is today

  • Specific fields we want to make “searchable” - as defined by the customer, we will save their hash value alongside the encrypted data.

  • Hashing will be done using SHA-256, and will include a secure random generated salt of 32 characters, which will be added to the value.

  • The salt is unique and will not be used anywhere else in the platform.

  • When the user enters a string to search, we will hash that value using all the salt values, and search those hash values.

Illustration of data flow when searching in Emedgene platform:

Illustration of data flow when creating a case with searchable field in Emedgene platform:

Appendix

Appendix: Control flows text

Write:

Client->Emedgene API: Add New Test Request 
note right of Emedgene API: Process Request 
Emedgene API->Key Vault: PHI 
note right of Key Vault: Encrypt 
Key Vault->Emedgene API: Encrypted PHI 
Emedgene API->Emedgene DB: Store Encrypted PHI

Read

Client->Emedgene API: Get Test Request 
emedgene DB->Emedgene API: Encrypted PHI 
Emedgene API->Key Vault: Encrypted PHI 
note right of Key Vault: Decrypt 
Key Vault->Emedgene API: Decrypted PHI 
Emedgene API->Client: Decrypted PHI

Write Searchable

Client->Emedgene API: Add New Test Request 
note right of Emedgene API: Process Request 
Emedgene API->Key Vault: PHI 
note right of Key Vault: Encrypt 
Key Vault->Emedgene API: Encrypted PHI 
Emedgene API-> Emedgene DB: Get Salt 
Emedgene API-> Emedgene API: Hash Value using Salt 
Emedgene API->Emedgene DB: Store Encrypted PHI + Hashed value

Read Searchable

Client->Emedgene API: Search string 
Emedgene API->AWS Secrets: Get Salt 
Emedgene API-> Emedgene API: Hash string using Salt 
Emedgene API->Emedgene DB: Search hashed string 
Emedgene DB->Emedgene API: Search results 
Emedgene API->Client: Search results

\

Manage Azure Blob data storage

Update Azure Blob Storage Credentials

See the table below to learn where to look for them in your Azure account.

Emedgene Setting
Corresponidng client (Azure) Setting

CLIENT_ID

application_id.

Format: ########-####-####-####-############

(letters/numbers)

CLIENT_SECRET

Value of the client_secret tuple (Value, Secret ID).

Format: #####-#######-######-######

(letters/digits/special chars)

TENANT_ID

ID of the tenant.

Format: ########-####-####-####-############

(letters/numbers)

ACCOUNT_NAME

An arbitrary name that the customer must supply to define the ACCOUNT_URL.

Format: string

CONTAINER_NAME

An arbitrary name that the customer must supply to define the ACCOUNT_URL.

Format: string

ACCOUNT_URL

The account_url of the Azure account.

Format: https://account_name.blob.core.windows.net/container_name


Blob Integration Setup

Create an App registration

  1. In Microsoft Entra ID, click on App registrations.

  1. Select New registration.

  2. Fill the name of the application & press "register."

  3. You got to the registered app page: (CLIENT_ID / TENANT_ID) From this you can retrieve: Application ID and Tenant ID. Both are marked in the screenshot.

  1. Press "Certificates & secrets"

  2. Press on "New Client secret"

  1. Fill the "Description" and change expires to 12 months. (or according to your organization policy), than press "Add"

8. Get the CLIENT_SECRET from this page.

  1. Give this App registration roles and read access to the relevant Blob.

Azure Blob configuration

  1. Go to Azure Storage accounts

  1. Get into the relevant Storage account

  1. Press on "containers"

  1. Press on the relevant container

  2. Press on "Properties"

  3. Copy the ACCOUNT_URL\


For Internal support:

Errors for bad connections can be found in CloudWatch on particular FRY log stream

Search for: BlobApi, BlobFs, azure.

Follow the instructions on the if needed.

Go to the BaseSpace and login.

Go to the nine-dot app launcher icon located on the left of the and select Curate from the dropdown menu.

However, if you have an Enterprise account and you would like Emedgene managed DRAGEN solution to save the DRAGEN output files in your own bucket, reach out to and follow this steps:

Emedgene directly from your AWS S3 bucket. In order to do it, you should enable for the Emedgene application URLs.

Emedgene managed DRAGEN solution saves the DRAGEN output files in a detected AWS S3 bucket that you have access to using your .

Emedgene directly from your AWS S3 bucket. In order to do it, you should enable for the emedgene application URLs.

Download and install the Google Cloud SDK from the Google Cloud SDK Install page.

is a cloud service that provides a secure way to store and manage sensitive information like API keys, passwords, and certificates. It offers robust features for key management, including key generation, storage, and lifecycle management.

(KMS) allows you to create and control encryption keys used to encrypt your data across a wide range of AWS services and applications. It provides centralized management of encryption keys and integrates seamlessly with other AWS services.

Before you proceed to this article, make sure you understand .

In > Management Tab, add or edit the required credentials: CLIENT_ID, CLIENT_SECRET, TENANT_ID, and ACCOUNT_URL.

BaseSpace CLI Installation Page
developer portal
Top navigation panel
techsupport@illumina.com
visualizes data in IGV
CORS
S3 credentials
visualizes data in IGV
CORS
LINK
Azure Key Vault
AWS Key Management Service
data storage management basics
Settings
Via Command Line
Via BaseSpace Developer Portal

Add a new case

This section will guide you through adding new cases to the Emedgene platform.

Please follow the steps as described below:

Caution: Please note that refreshing or leaving the page, exiting the Add new case tab, or power failure of your computer before you've completed adding a new case will result in loss of the case creation progress.

  1. The page is divided into two panels: Create family tree (left) and Add patient information (right).

  1. In the Create family tree panel (left):

    • Add Clinical Notes (optional) in a free text panel. In this section, you can record additional clinical information that does not fall under the other categories or provide further details that can give context and help solve the case.

    • You have an option to upload a file that includes description of the clinical presentation (.pdf, .xls, .txt, .doc, .jpeg, .jpg formats are supported). HPO terms for Phenotypes and Diseases are extracted from the files and can be added to Proband's Phenotypes in Patient info section.

    • You may select suspected Inheritance mode(s). This is for the case record and won't be used during analysis.

  1. In the Add patient information panel (right) for each of the family members:

    • Fill in a sample name (for cases starting from VCF, this must correspond to the corresponding proband or family member header within the file);

    • Click Next to proceed to the Case info screen.

  1. In the Case info screen:

    • Select case type (Array, Custom Panel, Exome, Whole Genome, or other). When running cases as Exome, variants outside exons ±50 bp are filtered out and won't appear in the results.

    • Pick whether you want Carrier Analysis to be carried out (checkbox). Carrier analysis requires you to provide us with a targeted genes list.

    • Sequencing Information (Choose from existing kit, No kit). You can indicate if there was an Enrichment Kit used if you wish to compare the breadth and depth of coverage to that expected for the kit used. RefSeq coding regions will be used as a reference if no kit is provided. This option is relevant for Custom Panel and Exome case types. In the Kit info section, fill in the Enrichment Kit and optionally Lab, Machine, Sequencing reagents, and Expected coverage.

    • Optional: Additional case info:

      • Indication for testing. Add free-text notes.

      • Label. Add labels to your case. You can choose among the labels created beforehand by your organization's manager. Labels cannot be added after case creation.

    • Summary: confirm the selected case type and genes list before completing case creation.

    • Click Next to complete case creation.

Caution: Pressing Next at this stage will create a case, so please ensure that you've carefully checked all the information. After the case is delivered, you will only be able to edit the Proband phenotypes.

  1. In the Done screen:

    • The Case ID is displayed;

Case details

Case details panel is divided into three tabs:

  • Case Info

  • Family Tree

  • Activity

How to see case details

Information presented on the Case details panel:

Case Info

1. Technical details:

  1. Case ID

  2. Case Type: Custom Panel, Exome, Whole Genome

  3. Sample Type: FASTQ, Project VCF, VCF, BAM

  4. Gene List - all genes or a particular gene list used to filter the analysis results

  5. Human Reference - the genome reference used during case analysis

2. Operational details:

  1. Ordered by - user who created the case by default, and creation date

  2. Signed by - user who finalizes the case

  3. Related cases - lists the Case IDs for all the cases that share one or more samples with the one currently selected

  4. Due Date - a deadline for finalizing the case. You can enter or edit the Due Date by clicking on the calendar icon under the Due Date section.

  5. Participants - names of the users involved in the case submission, analysis, finalizing, or those who subscribed to receive updates on the case. To receive email notifications on your colleagues' activities in the particular case, click on the Subscribe icon.

3. Clinical details:

  1. Patient Information: Sex (33.0+) / Gender (32.0 and older), Age

  2. Clinical Information:

    1. Proband Phenotypes - HPO terms used to describe clinical findings in the proband

    2. Suspected Disease: Suspected disease (if provided), Penetrance (%) and Severity (mild, moderate, severe, or profound)

    3. Parental Consanguinity

    4. Report secondary findings (Yes, No or N/A)

  3. Clinical Note: any notes on proband's phenotypes, family history, or other critical points of the case.

Family Tree

Here you can find:

  1. Sample information for each family member:

    1. Phenotypes: proband phenotypes and phenotypes reported for other family members (related and unrelated)

    2. Medical Condition (Healthy or Affected)

    3. Sex

    4. Age

    5. BAM file location

Activity

You can choose All activities, Comments, or Case-related activities from a dropdown menu. To add a comment to the case, write it in the Write a new comment text field and click Add.

Cases tab

The Cases tab provides a bird's-eye view of all the previously submitted genomic sequencing cases.

The Cases tab includes:

Browse and select cases

How to open a case

To open a case, mouse over the corresponding row in the Cases table and click on the Open case text next to the Case ID (first column). Alternatively, once a row is selected, clicking on it again will open the case as well.

How to filter cases

Go to Filters, select the field under Field, then choose or manually input value under List and click on Apply. To add another filter, click on Add new.

To remove a filter, under Active filters, click on the cross icon on the right of the filter setting. To clear filters altogether, click on the cross icon on the right of Filters.

Available filters include:

  • Case Id

  • Participants - users involved in the case submission, analysis, finalizing, or those who subscribed to receive updates on the case.

  • Type: Custom Panel, Exome, Whole Genome

  • Sample Id

  • Resolved: Resolved, Not Resolved

How to sort cases

You can sort cases by:

  • Creation date, or

  • Due Date.

To do this, hover over the column name and click on the up or down arrow to sort ascending or descending, respectively. The current sorting order is depicted as a single up or down arrow symbol next to the column's name.

Alternatively, you can click on the name of the column and select Sort ascending or Sort descending in the dropdown menu.

How to search for cases

You can use the Case search tab in the top bar to search for cases by the Case ID or Proband ID.

How to group cases

To group cases by Case Status, go to Group and select Status; to undo grouping, select None.

How to tweak Cases table view

Select fields to be displayed

A. Select fields to be displayed: go to Fields and set a toggle switch next to each field name in on or off position per your desired view.

B. Hide the currently displayed field: click on its title and select from the dropdown menu Hide column.

Change column order

A. Drag and drop columns: hover over the column title cell, click on the six-dot icon on the left to the text, drag to the desired location and drop.

B. Set column order under Fields: go to Fields, hover over the field name, click on the six-dot icon on the left to the text, drag to the desired location and drop.

C. Move a particular column: click on the column title and select from the dropdown menu Move left or Move right.

Change column width

Grab the right or left border of the column title cell and drag it with your cursor to the desired width.

​ ​

Cases table

Cases table lists all the genomic sequencing cases submitted by your organization. It is the primary component on the left-hand side of the Cases tab.

Brief column description:

Case ID

A unique ID assigned to a case by Emedgene.

Proband ID

Proband's sample ID submitted by creating the case in the platform.

Status

Creation Date

Automatically saved.

Due Date

Can be set, changed or removed on the spot. To set a date, click on the calendar icon and select a date of interest. To change it, click on the previously set due date and select a new one. To remove the due date, click on the cross button next to it.

Phenotypes

Proband phenotypes as submitted by the user.

Participants

Users involved in the case submission, analysis, finalizing, or those who subscribed to receive updates on the case. To receive email notifications on your colleagues' activities in the particular case, click on Subscribe icon. To unsubscribe, hover over your initials and click on the cross button.

Type

Case Type (Array, Custom Panel, Exome, Whole Genome).

Label

Dedicated user groups

Click on the Add new case button on the .

At the page, select the file type for your case analysis. Click Next to proceed to the Family tree panel.

Build a using the visual tool;

Select whether you want in Proband to appear in the AI Shortlist analysis results (checkbox).

;

;

Select (All genes, Phenotype based genes, Existing gene list, Create a new gene list) - indicate if you want the analysis to be limited to a specified list of genes.

Select : We can implement different combinations of to be used for different case types (i.e. Presets for exome may be different from Presets for genome) as defined by your SOPs to further streamline case review.

🆕 34.0+: If the user does not select a Preset group, the system automatically assigns the to the case. The default Preset group is indicated by the word "default" in parentheses after its name.

Confirm (32.0+).

Add participants to your case - subscribe your colleagues to notifications on change.

Information on the currently selected case is displayed in the window that pops up when you click on the corresponding row of the . To close the window, click on the cross icon.

Maternal and Paternal

Graphic representation of the pedigree. More information about the symbols can be found .

Maternal and Paternal

This tab logs actions related to the selected case such as changes, variant tagging, ACMG pathogenicity, changes to an evidence graph, evidence notes, transcript changes for a specific variant, and comments added by users. Each log includes the date and time that each action was performed. We keep all logs for at least six years for full traceability.

window that pops up on the right when activated

on top

: Issue reported, Uploading, In progress, Reanalysis, Archived, Delivered, Confirmed, Approved, Pending Sequencing, or any other customized case status

Label: any customized

Current in the system. You can change Case Status without leaving the Cases table via a convenient dropdown.

Custom Case Statuses can be added in Settings>Management>Test Statuses>. Additionally, you can rearrange statuses by using drag and drop, and the order will be reflected in the Case Status dropdown featured in Cases table and .

Custom .

as defined in Settings > Management.

Top navigation panel
Select sample type
pedigree
Secondary findings
Add a sample
Fill in the required patient details
genes list
preset group
Presets
default Preset group
subject consent for extended sharing
Case status
Cases table
ethnicity
here
ethnicity
Case status
Cases table
Case details
Case navigation
panel
Status
Case label
Case Status
Case Statuses
Individual case page Top bar
Case labels
Select fields to be displayed
Change column order
Change column width

Create a family tree

Build a pedigree via the visual tool.

It is ideal that a proband selected for case analysis is affected and has disease phenotype(s).

You can add a Father, a Mother, a Sibling, or a Child to any family member, starting with the Proband. To do this, choose their icon, then click on the Add family member button in the bottom right corner of the pedigree builder to select a family member.

To delete a family member, choose their icon, then click on the Delete Subject button in the top right corner of the Add patient information panel.

Note: There is no technical limit on the size or number of generations for a family tree.

Select sample type

You can select the sample's file type from the given options:

  1. FASTQ: .fastq.gz, .fq.gz, .bam, .cram.

  2. Project VCF: .pvcf, .vcf, .vcf.gz, .pvcf.gz

  3. VCF: .vcf, .vcf.gz, .targeted.json, *.gt_sample_summary.json

Case status

Case status indicates the current stage of case processing by the Emedgene platform or a genomic analyst.

Where can I find the current status of the case?

Built-in statuses include:

1. Uploading

The sequencing file is being uploaded on the platform.

Note: The Uploading status cannot be manually altered.

2. In Progress

Case is running.

Note: The In Progress status cannot be manually altered.

3. Delivered

The running stage completed, and the case is now available for users for analysis and review.

4. Finalized

Analysis and review completed.

Status Finalized by design should be assigned manually after summarizing the analysis findings through the Case Interpretation widget. Specifically, when finalizing a case, you should indicate its end result:

  • Confidently Solved (Positive),

  • Likely Solved (Positive),

  • Further Investigation (Uncertain), or

  • Unsolved (Negative).

Confidently Solved, Likely Solved and Further Investigation end result categories correspond to the Resolved case status supercategory, and Unsolved obviously falls into Not resolved (together with all the non-finalized cases). The indicated case analysis outcomes are used to calculate the diagnostic yield.

5. Archived

Indicates that the case is not subject to further review. Changing Case status to Archived requires technical support (pre-34.0 flow).

Note: The Archived status cannot be manually altered.

6. Move to trash 🆕 34.0+

Makes the case unaccessible. This status is only assigned manually.

Note: Once moved to trash, the Case status cannot be altered without technical support.

7. Pending Sequencing

The case has been created, but is not connected to any genetic data.

Note: The Pending Sequencing status cannot be manually altered.

8. Issue Reported

The case failed to run. Please check the integrity of the files used and verify that the variant caller is on our accepted variant caller list.

Note: The Issue Reported status cannot be manually altered.

9. Reanalysis

The system is re-running the AI Shortlist algorithm for the case.

Note: The Reanalysis status cannot be manually altered.

How to change the Case status

  1. In the Individual case page Top bar, click on a dropdown icon next to the current case status.

  2. Select the status from the menu.

  1. In the Cases table, click on the current case status.

  2. Select the relevant status from the dropdown menu.

Where can I manage Case statuses?

Supported Variant callers

Emedgene provides the tightest integration with DRAGEN for germline variation analysis, providing accuracy, comprehensiveness, and efficiency, spanning variant calling through interpretation and report generation.

Compatibility with DRAGEN and DRAGEN Array Variant Callers

DRAGEN
Emedgene
Available Callers

V36.0

SNV, CNV, STR, SV (del/dup/ins), Targeted, MRJD, JSON PGx*

V35.0

SNV, CNV, STR, SV (del/dup/ins), SMN, JSON PGx*

4.2

Recommended: V34.0

SNV, CNV, STR, SV (del/dup/ins), SMN

4.0

Recommended: V34.0

SNV, CNV, STR, SV (del/dup/ins)

3.10

Recommended: V34.0

SNV, CNV, STR, SV (del/dup/ins)

3.6-3.9

Recommended: V34.0

SNV


DRAGEN Array
Emedgene
Available Callers

1.2

V37.0

Cyto

Extensive Compatibility with Additional Variant Callers

The Emedgene platform supports a variety of variant callers and applies specific quality parameters for each. The quality assessment is an essential step in the Emedgene pipeline because variants with low quality will not be considered by the AI components.

If the variant caller is not supported or not recognized, a default quality function will be applied. The default parameters are built on GT (genotype), depth (DP) and allele bias (AB). These fields are mandatory, and their absence will induce “Low quality” for all variants.

The following variant callers are currently supported on the Emedgene pipeline, providing a header with the variant caller command line should be present within the VCF headers.

Additional callers can be supported on demand.

Var caller / VCF
Supported versions
Notes
Calling Methodology

N/A

Affymetrix Extensible Data. converted to VCF

CNVReadDepth

5.12, 5.20

SmallVariant

N/A

SmallVariant

1.38

CNVReadDepth

Clair3

V37 & up

SmallVariant

N/A

SmallVariant

ClinSV

N/A

SVSplitEnd

N/A

CNVReadDepth

CNVReporter

0.01

CNVReadDepth

1.0

CNVReadDepth

N/A

CNVReadDepth

cuteSV

2.02

V37 & up

SVSplitEnd

Multi-Sample Viewer:1.0.0.71

Unknown

1.0.0

SmallVariant

N/A

SVSplitEnd

0.1

CNVReadDepth

ExomeDepthAM

0.1

Private fork of ExomeDepth

CNVReadDepth

N/A

SmallVariant

3, 3.4, 3.5, 2014, 4, 4.1

SmallVariant

N/A

SmallVariant

Scramble

Running: scramble2vcf.pl

SmallVariant

1.4

SmallVariant

4.x, 5.x and not: 5.12, 5.20

SmallVariant

5.16

CNVReadDepth

2.2.0

SVSplitEnd

N/A

SmallVariant

2.X

SmallVariant

2.1.1

SVSplitEnd

2.2.4

SmallVariant

2.2.4

SVSplitEnd

2.X

SVSplitEnd

5.2.9

SmallVariant

201808, 201911, 202010

SmallVariant

201808.03

SmallVariant

2.0.6, 2.0.7, 2.5

SVSplitEnd

0.0.2

SmallVariant

2.0.1

CNVReadDepth

Spectre

V37 & up

CNVReadDepth

2.4.5

SmallVariant

N/A

SmallVariant

N/A

SVSplitEnd

Internally the list is also called a list of Emedgenizer / Emedgenizers. &#xNAN;Emedgenizer means to normalize a VCF to an expected format for the system.

Family tree legend

Family tree legend:

  1. Icon fill color in other pedigree members indicates the presence or absence of the proband's phenotypes in a present sample (regardless of the potential presence of additional unrelated phenotypes):

2. Icon color intensity denotes whether sample files have been uploaded for the particular individual:

3. Icon line type indicates whether the sample is considered or excluded during analysis (relevant to samples with uploaded files only):

​

Add a sample

You can choose one of the following options:

  1. Existing sample - pick one of the samples already loaded on the platform

  2. Upload New Sample - upload files from your PC and enter sample name

  3. Choose from storage - choose files from your cloud storage and enter sample name

  4. No sample - postpone uploading files but proceed with case creation or skip uploading files for family members other than Proband

Note: A case won't run if Proband sample files are missing. However, sample files are not mandatory for the rest of the family members (although highly recommended).

Note: When you are loading sample files from your PC or choosing them from the storage, and there is more than one file per sample, please ensure that all the necessary files are simultaneously selected in the upload pop-up. You may only select one file type per case (i.e. you may not select both a .vcf and a .bam at the same time).

> Family tree screen > Create family tree panel

More information about the pedigree symbols can be found .

> Select sample type screen.

Status column of the ;

;

.

Note: access to applying or Finalized status could be restricted to specific users, such as organization managers and directors, who possess corresponding .

Note: You can change statuses Delivered and (provided you have the necessary ) Finalized, as well as custom statuses. However, the default case statuses Uploading, In Progress, Archived, Move to trash, Pending Sequencing, Issue Reported and Reanalysis cannot be manually altered.

A. On the :

B. In the :

From Settings>Management>Test Statuses>, you can create custom Case statuses, remove unused Case statuses, and rearrange their order.

4.3

4.2

CNV

GATK

CNV

While adding a new case, you will build a pedigree and annotate each of the samples with data required for analysis ( > Family tree screen).

After the case has been created, the family tree is available in the panel (righthand panel of the Cases page).

> Family tree screen > Add patient information panel > Add sample section

Add new case page
here
Add new case page
Cases table
Case details panel
Individual case page Top bar
changing
user roles
roles
Individual case page
Cases table
Case Statuses
* Filled - the individual is affected by all of the proband's phenotypes;
* Half-filled - the individual is affected by some of the proband's phenotypes;
* Empty - the individual is not affected by any of the proband's phenotypes.
* Full color - the sample has files loaded in the case;
* Faded color - no sample files are available.
* Solid - the sample is included in the analysis;
* Dashed - the sample is ignored by Inheritance filters and the AI Shortlist algorithm, but you still can explore its genotypes.\
  ​
See full compatibility table
AED
ION AMPLISEQ
Atlas-SNP2
CanvasCNV
QIAGEN CLC Genomics Workbench
CNVKit
CnvXhmm
CNVnator
CytoScanHDArray
DeepVariant
eKLIPse
ExomeDepth
Freebayes
GA
TK
Mutect
GATKScramble
GLNEXUSSNV
IONTorrent
IONTorrent
MELT
Mity
NextGene
cuteSV for ONT
PAV
PAVSV
PBSV
Pisces
Sentieon
SentieonDNAScope
Sniffles
Sophia
SophiaCnv
Starling
Strelka
Witty
Add new case page
Case details
Add new case page

Adding patient info for the non-proband samples

1. Fill in the boxes:

Note: The fields marked with (*) are mandatory.

Note: Please omit the Patient ethnicities field for non-proband samples.​

1. Sex (33.0+) / Gender (≤32.0) (*)

Options: Male, Female, Unknown.

2. Relationship

Indicates the family relationship of a subject to the Proband automatically inferred from the pedigree. Options: Father, Mother, Sibling, Child, Other.

3. Date of Birth

Expected format: mm/dd/yyyy.

4. Ignore Sample

Mark the checkbox if you want to exclude the sample from the AI Shortlist analysis and Inheritance filters while preserving genotype data.

5. Add Proband's phenotypes

If a sample shares some phenotypes with the Proband, you can copy them by checking this box. Proband's phenotypes will appear in a newly created Related Phenotypes section. To remove any of the proband's phenotypes not observed in a current individual, click the ☒ button next to the HPO term in the Related Phenotypes section.

Note: A popup notification will appear at the bottom of the page if any input HPO term or HPO ID is unknown.

6. Unrelated Phenotypes

Selection mode

Please follow the steps described below for each phenotype:

  • Enter an HPO term (e.g., Hypoplasia of the ulna), an HPO ID (e.g., HP:0003022), or a descriptive phenotype name (e.g., Underdeveloped ulna) in the search box;

  • Select a matching term from a dropdown menu and press Complete after you've added all the terms.

Batch mode

Paste a list of comma-separated HPO terms or HPO IDs (🆕 32.0+) in the search box and press Complete.

2. Click on Complete once all the information is added.

Secondary findings

While creating a case, you can choose if you want Secondary (Incidental) findings in the Proband to appear in the results.

These are known or expected pathogenic variants in the genes that are unrelated to the primary purpose of the testing. The secondary finding genes list includes:

Labeling a case

Version 33.0+:


Versions older than 33.0:

Once a case is created, Case labels cannot be removed or added.

Gene list

Select gene list

You can limit analysis to a gene list in the platform while creating a case. Choose between:

1. All genes

No limitation of the analysis.

2. Phenotype based genes

The list is automatically built from genes related to the HPO terms you entered for the case (per Emedgene knowledge base).

3. Existing gene list

Select one of the previously added gene lists from a dropdown list.

4. Create a new gene list

Note: Please use the up-to-date gene symbols approved by the Hugo Gene Nomenclature Committee. When adding gene symbols in a Batch mode, those genes that do not comply with HGNC standards will be automatically excluded from the gene list. These genes will appear for 3 seconds in a black error box at the bottom of the screen.

Selection mode

For each gene please follow the steps described below: Enter a gene symbol in the search box in the right panel (Candidate Genes) and select a matching symbol from a dropdown menu.

Batch mode

After selecting batch mode, paste a list of comma-separated gene symbols in the search box in the right panel (Candidate Genes).


Gene list modes

You can choose between two different modes of a gene list feature:

1. Gene panel mode

The default option.

Analysis is limited to the selected gene panel, no variants in other genes are considered in the results. If this in silico panel is used for analysis of exome or genome data, the gene restriction may be lifted during manual analysis to "open-up" the entire exome or genome for analysis.

2. Boost genes mode

Enabled through checkbox.

Analysis is performed for variants in all the genes. Variants in the targeted genes get upgraded scores during prioritization by the AI Shortlist algorithm.


How to filter variants by a gene list

1. Candidate Genes filter

2. Gene Lists filter created in a case

3. Gene Lists filter created in Settings

First, fill in the List title and click Add button. Then add the gene symbols one by one (Selection mode) or in a batch (Batch mode).

  • Selection mode - for each gene please follow the steps described below: Enter a gene symbol in the search box (Candidate Genes) and select a matching symbol from a dropdown menu.

  • Batch mode: Paste a list of comma-separated gene symbols in the search box (Candidate Genes).

When you finished, press Save.

To view the Gene list in read-only mode, click on its name. By pressing the corresponding icons next to the Gene list's name, you can duplicate, edit or delete it. If a gene list has already been used by a case in the platform, you will only have the possibility to duplicate it.

Supported parental ethnicities

Ethnicities of the proband's mother and father can be specified during the UI case creation. Starting from version 32.0.0, this can also be accomplished via API case creation. Please refer to the following list of supported ethnicities.

Individual case page

The Individual case page includes:

Highlights a shortlist of variants, suggested to be reviewed first - Most Likely Candidates and Candidates.

Illustrates quality metrics for the sequenced samples.

Provides numerous customizable filters to help you explore the total list of genetic variants in compliance with your organization's standard case review process. You can export shortlisted variants in .xlsx format.

Documents versions of all the resources used during case analysis.

CSV format requirements

General CSV format requirements

The following are the general format requirements for a CSV file used to create multiple cases:

  1. The file must have a .csv extension.

  2. The file must contain a [Data] header.

  3. The row after [Data] header must include the field names identifying the data in each column. The column names are case-sensitive.

  4. The row after the column name header and each subsequent row represents a sample.

  5. Each column represents a data field.

  6. It is essential that there are no empty rows between the [Data] header and the last sample row.

  7. Number of cases per file can’t be greater than 50.

  8. On versions before 34.0, cells should not contain commas. Consider replacing the commas with semicolons.


CSV schema

1. Mandatory fields

Must be present in the sample table at all times.

  1. Case Type;

  2. Family Id;

  3. Phenotypes OR Phenotypes Id.

2. Conditionally mandatory fields

If these fields are left empty, it will result in the creation of an empty sample.

  1. BioSample Name;

  2. Files Names;

  3. Storage Provider Id;

This field is mandatory if Files Names is empty:

  1. Sample Type.

This field is required if the "auto" option is used for Files Names (only relevant for BSSH):

  1. Default Project.

3. Optional fields

The sample table may include these supported optional columns.

  1. Boost Genes;

  2. Clinical Notes;

  3. Date Of Birth;

  4. Due Date;

  5. Execute now;

  6. Gender;

  7. Gene List Id;

  8. Kit Id;

  9. Label Id;

  10. Opt In;

  11. Relation;

  12. Selected Preset;

  13. Visualization Files.

4. Custom fields

The sample table may contain custom columns to suit your specific needs and include any relevant information that is important for your workflow.

Note: In cases with more than one sample, custom fields are only recognized and added to case information if their values appear within the same table row where the Relation field is equal to "proband".

Custom field examples:


Batch case .csv file validation rules

Required BSSH file path format:

For BSSH, it is necessary to use the actual names (numbers):

instead of aliases

Human-Readable Path for BSSH files in Batch CSV (Version 37)

In version 37, we introduced an enhancement to the batch upload process that allows customers to provide a human-readable path in their batch CSV for BSSH files.

Validations

When a batch CSV includes a human-readable path, the system performs the following validations for paths in BSSH storage:

  1. Single File in the Path:

    • If the provided path contains exactly one file or dataset, the batch upload proceeds successfully.

  2. Two Files in the Path:

    • If the path contains two files with the same name (for example, two pairs of fastqs in a dataset) , the system will:

      • Select the dataset marked as QCPassed.

      • Fail the batch upload if both datasets are marked as QCPassed, as this indicates conflicting data.

  3. More Than Two Files in the Path:

    • If the path contains more than two files or datasets, the system fails the batch upload, as the path is considered ambiguous or invalid.

Error Scenarios

  • Multiple QCPassed Datasets: If two datasets in the same path are marked as QCPassed, the batch upload will fail with a descriptive error indicating the conflict.

  • Excessive Files in the Path: If more than two files are found for the provided path, the batch upload will fail, instructing the user to provide a more specific or valid path.

Benefits

  • Enables customers to use intuitive, human-readable paths in their workflows.

  • Automatically handles dataset selection based on quality control status.

Candidates tab

The Candidates tab presents:

A shortlist of the most promising variants with the highest scores from the AI Shortlist:

  • before 30.0: SNVs;

  • 30.0+: SNVs and CNVs;

  • 32.0+: SNVs, CNVs, SVs, mtDNA variants and STRs.

These variants are initially selected by the AI Shortlist, but you may untag variants or tag them manually during the case review.

Pathogenic or likely pathogenic variants in the medically actionable genes defined by the ACMG. These variants are automatically tagged only if you've selected the Secondary findings checkbox while creating a case.

Carrier

Variants identified by the Carrier analysis pipeline. Carrier variants are automatically tagged only if you've selected the Carrier Analysis checkbox while creating a case. Analysis requirements and a list of targeted regions are specified by the organization's manager. This Carrier analysis flow is implemented by request.

Variants that were manually selected to be reported.

Reviewing the Candidates tab

To select variants with a particular tag, use the Filter candidates dropdown menu in the top right corner. You can choose between Most Likely, Candidate, Incidental, Carrier, Not Reviewed, or any custom tags used in your organization.

For each variant on the Candidates tab, you can explore the suggested diagnosis, gene symbol, main variant details, and variant tag.

When a variant is found in a gene with no known association with a disease, the possible diagnosis cannot be indicated. Such variants are displayed under the Gene of Unknown Significance title.

Adding patient info for the proband

1. Fill in the boxes:

Note: The fields marked with (*) are mandatory.

1. Sex (33.0+) / Gender (≤32.0) (*)

Options: Male, Female, Unknown.

2. Relationship

The default fixed value for Proband is Test Subject.

3. Date of Birth

Expected format: mm/dd/yyyy.

4. Medical Condition (*)

Options: Affected, Healthy.

The default value for Proband is Affected, but you may change it to Healthy.

5. Proband Phenotypes (*)

To add all relevant phenotypes for the Proband, use one of the following methods:

Note: the maximum permissible number of Proband Phenotypes is 100.

Selection mode

Please follow the steps described below for each phenotype:

  1. Enter an HPO term (e.g., Hypoplasia of the ulna), an HPO ID (e.g., HP:0003022), or a descriptive phenotype name (e.g., Underdeveloped ulna) in the search box.

  2. Select a matching term from a dropdown menu and press Complete after you've added all the terms and additional patient information below.

Batch mode

Paste a list of comma-separated HPO terms or HPO IDs (🆕32.0+) in the search box and press Complete.

Notes:

  • A popup notification will appear at the bottom of the page if any input HPO term or HPO ID is unknown.

  • Only phenotypes from the 'Phenotypic abnormality' HPO branch are currently supported.

Extract HPO terms from the file uploaded in the Clinical Notes section

In the Clinical Notes section upload a description of the clinical presentation in .pdf, .xls, .txt, .doc, .jpeg, or .jpg format. Among the extracted HPO terms for Phenotypes and Diseases select the ones you want to add to Proband's Phenotypes.

6. Proband Suspected Disease Condition.

Enter the disease name in the search box, select a matching term from a dropdown menu and press Complete. All the associated phenotypes will be automatically added to the Proband Phenotypes. To remove any phenotype described for the disease but not observed in your patient, click the ☒ button next to the HPO term in the Proband Phenotypes list.

7. Suspected Disease Penetrance

Enter the suspected disease penetrance as a percentage.

8. Suspected Disease Severity

Select the appropriate category to indicate the severity of the disease symptoms observed in the patient: Mild, Moderate, Severe, Profound.

9. Consanguinity

Mark the checkbox if applicable.

10. Patient Ethnicities

2. ​Click on Complete once all the information is added.

> Family tree screen > Add patient information panel > Patient info section

Phenotypes not shared with a Proband. They can be added one by one () or in batch ().

> Family tree screen > Create family tree panel > Show Secondary Findings

81 genes () on versions 33.0+;

78 genes () on versions <33.0.

With version 33.0 and later, you have the flexibility to manage Case labels at any time: create, add, or remove them directly in the .

The organization's custom Case labels must be assigned while creating a case, in the Case info screen of the flow.

The desired Case labels should be created prior to case creation by the organization's manager in the .

> Case info screen > Select genes list

Generate a new virtual panel: add a List title and then add all the gene symbols one by one () or in a batch ().

To filter variants by the gene list, or remove the gene list restriction after the case has been delivered, go to the > > > Candidate Genes filter.

If you have run a case in All genes mode, you still can filter variants by a gene list. Go to > > Gene Lists and select a list of interest. The Gene Lists filter presets can be defined by organization's manager.

Alternatively to creating a gene list filter in Presets, create and manage gene lists in > Management > Gene lists.

You can enter a specific case from the by clicking Full details in the corresponding row of the case table.

Displays a Case ID and and includes Case interpretation, Edit case info, and Report preview buttons.

Each custom field must be assigned a unique name without spaces. Data from custom columns is saved per case under the Additional information section of .

Field (column) name
Expected input
Field details
Example

(highlighted in red), (highlighted in orange), and fields should be filled in according to the following rules.

Field (column) name
Expected input
Field details
Example

In Report and other custom

All the relevant fitting a сompound heterozygous mode of inheritance are presented together. This refers to both confirmed and assumed compound heterozygosity (cases with at least one parent and singleton cases, respectively).

If you want to inspect the complete variant information, click on the variant bar to continue to the . You can visualize evidence in text or graphical format (Click on the interactive text in the top left corner: Show evidence as text or Show evidence graph to toggle between the two).

> Family tree screen > Add patient information panel > Patient info section

,

,

, or

Automatically infer disease-associated phenotypes (see below).

Note: If consanguinity is identified in the Proband's parents, but this box is not selected in case creation, this will result in a discrepancy alert in the .

Paternal and Maternal. Enter the name in the search box and select a matching term from a dropdown menu.

Add new case page
Add new case page
Miller et al. 2023
Miller et al. 2022
Cases table
Add new case
Organization settings
Add new case page
Analysis tools
Filters
Gene Filters
Analysis tools
Presets
Settings
Selection mode
Batch mode
Selection mode
Batch mode

A "Afghan Jews" "Afghani" "African" "African American" "Afro-Brazilian" Alaska Native" "Algerian" "Algerian Jews" "Amish" "Anatolian" "Arab" "Argentinian/Paraguayan" "Armenian" "Ashkenazi Jews" "Asian" "Asian Brazilian" "Australian Native" "Azerbaijan Jews"

B "Bedouin" "Bengali/Northeast Indian" "British/Irish" "Bulgarian Jews"

C "Caribbean Australian" 32.0.0+: "Caucasus Jews" "Central African" "Central Asian" "Chilean" "Chinese" "Chinese Dai" "Christian Arab" "Circassian" "Colombia"

D "Druze" "Dutch"

E "East African" "East Asian" "East European" "Egyptian" "Egyptian Jews" "Emirates" "Ethiopia" "Ethiopian / Eritrean" "Ethiopian Jews" "Ethiopian Jews - Beta Israel" "European" "European American"

F "Fijian Australian" "Filipino" "Filipino Austronesian" "Finnish" "French" "French Canadian"

G "Georgian Jews" "Germans" "Ghanaian / Liberian / Sierra Leonean" "Greece Jews" "Greek Americans" "Greek / Balkan" "Guam/Chamorro"

H "Hawaiian"

I "Iberian" "India - Bene Israel Jews" "India - Cochin Jews" "Indian" "Indigenous Amazonian" "Indigenous peoples in Canada" "Indonesian" "Inuit" "Iranian" "Iranian Persian Jews" "Iraq" "Iraqi Jews" "Irish" "Italian" "Italian Americans" "Italian Jews"

J "Japanese" "Japanese Brazilian" "Jordan"

K "Kenyan" "Korean" "Kurdish" "Kurdish Jews"

L "Latino/Hispanic Americans" "Lebanese Jews" "Levantine" "Libyan" "Libyan Jews"

M "Maasai" "Malayali Indian" "Melanesian" "Mesoamerican and Andean" "Mexican American" "Middle Eastern" "Mongolian / Manchurian" "Mormon" "Moroccan" "Moroccan Jews" "Muslim Arab"

N "Native American" "Nepali" "Nigerian" "North African" "North and West European" "Northern Asian" "Northern Indian"

O "Other Pacific Islander"

P "Pakistani" "Papuan" "Polynesian" "Portuguese in Northern Brazil" "Portuguese in Southern Brazil"

R "Russian Jews" "Russians"

S "Samaritan" "Samoan" "Sardinian" "Saudi" "Scandinavian" "Senegambian / Guinean" "Siberian" "Somali" "South African" "South Asian" "Southern East African / Congolese" "Southern European" "Southern Indian" "Southern Indian / Sri Lankan" "Southern South Asian" "Spaniards" "Spanish Jews" "Sub-Saharan African" "Sudanese" "Swedes" "Syrian Jews" "Syrian-Lebanese"

T "Tajikistan Jews" "Thai / Cambodian / Vietnamese" "Tunisian" "Tunisian Jews" "Turkish" "Turkish / Anatolian" "Turkish Jews"

U "Ukraine" "Ukraine Jews" " zbekistan/ Bukharan Jews"

V "Venezuela"

W "West African"

Y "Yemenite" "Yemenite Jews"

Institution

Free text

Custom

GenoMed Solutions

Sample_Received_Date

Free text

Custom

24-02-2022

Sample_Type

Free text

Custom

Amniotic Fluid

/projects/3824821/appresults/2319318/files/119675608
/projects/ABC_DEF_2022-12-22_DEv395/appresults/ABC-GM58342-def/files/ABC-GM58342-def.hard-filtered.vcf.gz
Cases page
Top bar
Case status
Candidates tab
Lab tab
Analysis tools tab
Versions tab
Case Info
Most Likely Candidates and Candidates
Incidental
variant tags
Most Likelies and Candidates
Evidence page
Add new case page
Lab tab
ethnicity
Mandatory
Conditionally mandatory
Optional
One by one (Selection mode)
In a batch (Batch mode)
Extract HPO terms from the file uploaded in the Clinical Notes section
Proband Suspected Disease Condition

Most Likely Candidates and Candidates

To streamline case review, the AI Shortlist pre-selects the list of variants likely to be causative for each case:

Most Likely Candidates

Variants that are most promising for solving the case. This list is limited to 10 top-scored variants but may include more if more than one variant is tagged per gene (suggesting compound heterozygosity). We can change the Most Likely Candidates number limit upon request.

Candidates

Several dozen highly scored variants worth considering.

As of version 30.0 and onwards, the ranking of variants by AI Shortlist considers both SNVs and CNVs, including SNV + CNV compound heterozygotes. Starting from version 32.0, AI Shortlist additionally considers SVs, mtDNA variants and STRs.

The AI Shortlist rates variants based on predicted variant effects, alternative allele frequency, familial segregation pattern, phenotypic match, in silico predictions, and other relevant information from scientific papers and databases.

During the case review, you can untag variants selected by the AI Shortlist or manually tag ones not selected by the AI Shortlist.

BioSample Name

Free text

Conditionally mandatory. An empty sample will be created if the field is left blank.

NA24385

Boost Genes

1. "TRUE" 2. "FALSE"

TRUE

Case Type

1. "Whole Genome" 2. "Exome" 3. "Custom Panel" 4. Array

5. Custom case type

Mandatory. Only considered for proband.

Whole Genome

Clinical Notes

Free text

Optional

A 14-year-old boy with a visual acuity of 20/200 in both eyes in whom hearing loss was first noted at 5 years of age on routine screening; audiometry revealed sensorineural hearing loss.

Date Of Birth

Date "YYYY-MM-DD"

Optional

2013-01-22

Default Project

Free text

Conditionally mandatory. Must be filled in if the "auto" option is used for Files Names (only relevant for BSSH).

GIAB

Due Date

Date "YYYY-MM-DD"

Optional

2023-05-03

Execute now

1. "TRUE" 2. "FALSE"

Optional. Default value is "TRUE". Use "FALSE" if you don’t want to run the case upon uploading the file.e Only considered for proband.

FALSE

Family Id

Free text

Mandatory

RM8392

Files Names

1. Semicolon-separated list of paths to .fastq, .fastq.gz, .vcf, .vcf.gz, .bam, .cram, *gt_sample_sammary.json files without spaces 2. "existing" 3. "auto"

/GIAB_cases/1/NA24385.dragen.hard-filtered.gvcf.gz;/QA_cases/Other/NA24385.dragen.cnv.vcf.gz;/QA_cases/Other/NA24385.dragen.repeats.vcf;

Sex / Gender*

1. "F" 2. "M" 3. "U"

Optional. Default value is "U".

*The field is labeled as Sex in versions 33.0 and later, and as Gender in older versions.

M

Gene List Id

integer

Optional. Must be the id of a previously defined Gene List. Only considered for proband.

12345

Kit Id

integer

Optional. Must be the id of a previously defined Kit. Only considered for proband.

23456

Label Id

integer

Optional. Must be the id of a previously defined Case Label. Only considered for proband.

34567

Opt In

1. "TRUE" 2. "FALSE"

FALSE

Phenotypes

  1. Semicolon-separated list of HPO phenotype terms

  2. "Unaffected" is used for non-affected family members.

Mandatory for proband sample if Phenotypes Id is empty. List must be under 100. It is possible to include non-HPO terms if Phenotypes Id is empty.

Abnormal pupillary function;Orthotopic os odontoideum;

Phenotypes Id

Semicolon-separated list of HPO phenotype IDs

Mandatory for proband sample if Phenotypes is empty.

List must be under 100.

HP:0007686;HP:0025375;

Relation

1. "proband" 2. "mother" 3. "father" 4. "sibling"

Optional. Default value is "proband". Values "proband", "father", "mother" can be only used once per Family ID. One sample with Relation "proband" is required per Family ID.

Mother

Sample Type

1. "FASTQ" 2. "VCF"

Conditionally mandatory. Required if Files Names is empty. Only considered for proband.

FASTQ

Selected Preset

1. Free text 2. "Default"

Optional. Must be the name of a previously defined Preset. If set to default, the default Preset will be applied. If left empty, no Preset will be applied.

High quality candidates

Storage Provider Id

Integer

Conditionally mandatory. Required if Files Names is not empty. Must be from the configured storage provider ID list.

208

Visualization Files

Semicolon-separated list of paths to sequence alignment data files of extension .bam, .cram; 🆕34.0+: also .tn.bw, .baf.bw, .roh.bed, .lrr.bedgraph, .baf.bedgraph

Optional

/giab_project/NA24385.bam

Batch case upload via CLI

Prerequisites

  • Emedgene platform version >= 32

Batch upload via CLI (Command Line Interface)

  1. Download the batch case create script. Replace my-domain with your Emedgene domain. Illumina cloud: my-domain.emg.illumina.com Legacy Emedgene cloud: my-domain.emedgene.com

curl https://my-domain.emg.illumina.com/v2/js/batchCasesCreator.js --output batchCasesCreator.js
  1. Download the CSV template file.

node batchCasesCreator.js saveTemplateFile
  1. Execute the batch cases creator as java script using the command below. Replace my-domain with your Emedgene domain and my-email with your user email. A prompt for your Emedgene password will appear, enter the password and press Enter.

node batchCasesCreator.js create -h https://my-domain.emg.illumina.com -c batchCases.csv -u my-email -l
  1. In case of validation errors in the input CSV, an output CSV called batchCases_results.csv will be created in the same location with detailed error results.

  2. -l will create a log file in the same location.

More information can be found by running

node batchCasesCreator.js --help
node batchCasesCreator.js create --help

Batch case upload from platform

If you're comfortable with scripting and API usage, you can upload multiple cases at once using those methods. But if you're not a technical expert, don't worry. There is a user-friendly alternative available in versions 32.0 or newer - importing a CSV file directly through the user interface.

Please follow the steps as described below.

Caution: Please note that refreshing or leaving the page, exiting the Add new case tab, or power failure of your computer before you've completed a batch case upload will result in loss of the case creation progress.

1. Prepare a CSV file

CSV (Comma-Separated Values) is a simple file format used to store data in tabular form. A row represents a sample, and a column represents a data field.

2. Upload a CSV file

  1. Click on the Switch to batch button in the top right corner. You'll be directed to the Select file page of the Batch upload flow. Note: Here you can download a CSV template in the valid format.

  2. Drag and drop a CSV file into the box or upload it from the file explorer. Wait for file upload and validation to finish.

3. Review file validation results

After validation is complete, you will be directed to the Batch validation page. It features validation results details for you to review:

  • File name,

  • Number of rows in the file,

  • Number of cases to be created

  • Number of errors found,

  • Status message:

    • if no errors were detected, a success message will be displayed;

* If any errors were detected, an error message will be displayed. You will be given the option to download a file with error details to help you diagnose and correct any issues with the data. Once you've corrected the CSV file, reupload it.

4. Create cases

  1. Click on Create. A progress bar will appear on the right as the cases are created (Cases creation page).

  2. If the cases have been created successfully, the Cases summary page will display the total number of cases that were created.

  3. If there were any errors during the batch case creation process, the Cases summary page will display a table indicating the number of cases that were successfully created and the number of cases that failed.

You will have the option to download a CSV file containing two additional columns: Errors and Case ID. The Errors column will contain error messages for samples where case creation failed, while the Case ID column will contain the Case ID of a successfully created case for the lines where case creation was successful.

Variant table

The Variant table:

  • Displays the analysis results, one variant per row;


Variant table legend (34.0+)

Starting from version 34.0, the formatting of variant table rows provides hints about the variant status for the current user per particular case. It indicates whether the variant has been viewed by the current user, and whether it has been tagged either by the current user or by the AI Shortlist.

Tagged vs not tagged variants:

  • Not tagged variants are indicated by black font color;

  • Variants tagged by the AI Shortlist are indicated by green font color;

  • Variants tagged by any user, whether currently active or another user, are shown in blue font color.

Viewed vs not viewed variants:

  • Variants viewed by the current user are indicated by regular font weight. The variant is marked as viewed only if the current user has opened the variant page before the case was finalized.

  • Not viewed variants are indicated by bold font weight.

Formatting of the Variant table row
Viewed by the current user?
Tagged?

no

no

no

by the AI Shortlist

no

by a user

yes

no

yes

by the AI Shortlist

yes

by a user


The table view is customizable:

  1. Any column can be shown or hidden by selecting the columns in the Show/Hide Columns menu (activated via an icon on 30.0.0+) in the top right corner of the page.

  1. You can choose between comfort and compact view by pressing the button next to the Variant search tab.

All modifications are automatically saved for each individual user and retained until new changes are made.

Variant table columns

Variant table columns:

Variant search

You can search for variants in the Variant search box by:

Single phenotype

"phenotype1" (e.g., "Mandibular prognathia")

Disease

"disease1" (e.g., Kabuki syndrome 1)

Disease inheritance mode

"inheritance mode1" (e.g., Autosomal dominant);

Genomic position

"coordinate1" (e.g., chr11:2686616)

Specific SNV/indel variant (32.0+)

"variant" (e.g., chr1:27089776G>T)

Genomic range

"range1" (e.g., chr11:2686616-2886620)

CNV length

"cnv_size:size1" (e.g., cnv_size:100000-10000000)

Gene symbol

"gene1" (e.g., BRCA1)

Multiple gene symbols added in batch

"gene1, gene2, gene3" (e.g., BRCA1, BRCA2, UBE3A)

Most of the above-listed options may be combined.

Individual case page: Top bar

Options available through the Top bar:

  • Reanalyze the case

Genome Overview

The Genome View Tab, available from V37.0 and up, is a powerful feature designed to give users a clear, visual overview of the genome and chromosomes in their cases. This feature is especially useful for analyzing large Copy Number Variation (CNV) events and regions of homozygosity/loss of heterozygosity (ROH/LOH) across the genome, providing intuitive filtering and interactive insights for researchers and clinicians.

What is the Genome View Tab?

The Genome View tab is a dedicated section within the Case Page for Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), and Array data. This tab offers a graphical visualization of genomic data, focusing on CNV and LOH/ROH analysis for proband cases. Users can access this tab directly from the Case Page.

Key Features

Chromosome Ideogram

The chromosome ideogram offers a visual representation of all 23 human chromosomes, with CNV and LOH/ROH events highlighted for intuitive analysis. Here's what you can expect:

Variant types:

  • Deletions (DEL): Marked in red, displayed to the left of the chromosome.

  • Duplications (DUP): Marked in blue, displayed to the right of the chromosome.

  • LOH/ROH (Regions of Homozygosity/Loss of Heterozygosity): Marked in gold, displayed over the chromosome.

Note: Variants with no coverage or reference (Ref) are excluded.

Filtering Options:

  • Users can filter segments by size, using a range selector with the following options: 50 bp,1 KB, 10 KB, 50 KB, 100 KB, 1 MB, 10 MB, Max (no filter).

  • The default filter is set from 50 KB to Max.

  • Limitation: Only the 500 largest variants are displayed in this tab in v37.0.

Hover and Click Interactions:

  • Hovering over a variant displays

    • Chromosome number, start and end positions, and size (e.g., chr1:100000-200000 (100 KB))

    • Cytoband range (e.g., p12.3 - q11.2) based on ISCN nomenclature

    • Variant type (DEL/DUP/LOH/ROH)

    • Number of genes affected

  • Clicking on a chromosome refines the genome view below to that chromosome.

  • Clicking on a variant opens a detailed Variant Page where many actions and further review can be made.

  • Legend: A clear legend explains color coding and icons for DEL, DUP, and LOH/ROH variants for quick reference.

Genome Viewer

The genome viewer provides a deeper dive into the genomic data through three interactive tracks:

  • Log R / TNS Track:

    • Displays copy number intensity data using values from the TNS BigWig file or LogR bedgraph.

    • Y-axis ranges from -3 to 3, with increments of 0.4.

    • X-axis displays the genome (whole genome view) or chromosome segments (whole chromosome view).

  • BAF Track:

    • Displays B Allele Frequency (BAF) data using values from the BAF BigWig file or BAFbedgraph.

    • Y-axis ranges from 0 to 1, with increments of 0.1.

    • X-axis aligns with the Log R track.

  • ROH Track:

    • Indicates regions of homozygosity for further analysis.

Zoom and navigation

  • Default View: Displays the entire genome.

  • Zoom-In Options: Users can zoom in to view individual chromosomes by clicking on them.

  • Interactive Navigation: Clickable chromosomes on the ideogram allow seamless switching between views.

Optional. Indicates whether the will be used. "TRUE" means that variants in the targeted genes will receive upgraded scores during prioritization by the AI Shortlist algorithm. Default value is "FALSE". Only considered for proband.

Conditionally mandatory. An empty sample will be created if the field is left blank. The "existing" option automatically locates FASTQ files based on the BioSample Name. Note: If data files for an existing case were sourced from the customer’s external bucket and later removed, attempting to create a case from those files will result in an error. With the "auto" option, BSSH users can automatically locate FASTQ files based on the BioSample Name and Default Project provided. When using BSSH without the "auto" option, ensure that your file path is .

Optional. Indicates whether the case subject consented to the with your network(s). Default value is "TRUE".

Download and install node js platform via Minimum version required: 16 Upgrade existing installation: nvm install --lts

Edit the downloaded batchCases.csv file. See for more details.

Start by downloading a CSV template with an example line and mandatory and non-mandatory fields from the Add new case page set to Batch mode (see ). Fill the file with your data according to .

Click on the + New case button on the .

Supports and sorting by various criteria;

Allows of up to 1500 filtered variants;

Enables users to variants to a delivered case.

Note: After a case , all variants appear as not viewed.

can be dragged-and-dropped.

Definition
Format Example

The Top bar in the Individual case page indicates the Case ID and current .

Change the

and write interpretation notes

Preview the

Boost genes mode
extended sharing of data
https://nodejs.org/en/download
CSV format requirements
Top navigation panel
variant search
downloading
manually add
reanalysis
Columns
formatted correctly
CSV format requirements
step 2
Case status
Case status
Finalize the case
Edit the case info
case report

Allele Bias - indicates the percentage of reads that include an alternate allele out of all reads. Available only for SNVs.

Allele Freq - indicates variant frequency category according to the highest allele frequency in public population frequency databases:

  • Private: 0;

  • Rare: <0.01;

  • Low Frequency: 0.01-0.05;

  • Polymorphism: >0.05.

🔻 Allows alphabetical sorting

Alternate Read - number of alternate reads.

Available only for SNVs.

🔻 Allows numerical sorting

Coding Change - variant's coding sequence change (transcript-specific).

Conservation - summarized nucleotide conservation score. Tip: you can glance at the underlying scores in the pop-up tooltip

Depth (in proband):

  • SNV/Indel - sequencing depth of coverage at the variant position;

  • CNV - depth of coverage across the CNV region.

🔻 Allows numerical sorting

Tip: hover over the partially displayed disease name to see the full name in the pop-up window

Emedgene DB Frequency - variant frequency in Emedgene's internal control database.

Father Depth:

  • SNV/Indel - sequencing depth of coverage at the variant position;

  • CNV - depth of coverage across the CNV region.

🔻 Allows numerical sorting

  • SNV/Indel - based on Base Quality, Depth, Mapping Quality, and Genotype Quality;

  • CNV - based on CNV Quality, Size, and Bin Count.

🔻 Allows alphabetical sorting

Gene:

  • SNV/Indel/single-gene CNV - an HGNC-approved gene symbol;

  • Multi-gene CNVs - a list of HGNC-approved gene symbols and number of genes included if only part of the list is shown. Tip: if only the beginning of the list is displayed in the table, you can see the full gene list in the pop-up tooltip.

gnomAD Het Count - number of gnomAD subjects who are heterozygous for this variant.

gnomAD Hom / Hemi - number of gnomAD subjects who are homozygous (autosomal or X-linked variant in a female) or hemizygous (X-linked variant in a male) for this variant.

Historic AF - variant frequency in the organization's pre-loaded Historic DB.

Known Variants - displays the variant's classification(s) in ClinVar and your own curated variant database.

Manual Classification - displays the user-assigned Pathogenicities from your previous cases. The color of each element indicates the variant's Pathogenicity, while a number corresponds to a number of the previous classifications. Tip: hover over the badge to see the Pathogenicity.

Mother Depth:

  • SNV/Indel - sequencing depth of coverage at the variant position;

  • CNV - depth of coverage across the CNV region.

🔻 Allows numerical sorting

  • SNV/Indel - based on Base Quality, Depth, Mapping Quality, and Genotype Quality;

  • CNV - based on CNV Quality, Size, and Bin Count.

🔻 Allows alphabetical sorting

Networks Classification - displays the Pathogenicities assigned by partnering organizations in your network. The color of each element indicates the variant's Pathogenicity, while a number corresponds to a number of the previous classifications. Tip: hover over the badge to see the Pathogenicity.

Phenomatch score - a score reflective of the phenotypic match between a patient's phenotypes and clinical presentation of one of the gene-related diseases (the one shown in the Disease column). The Phenomatch score is calculated by Emedgene's proprietary algorithm and ranges from 0 to 1.

Prediction - summarized in silico pathogenicity prediction score. Tip: you can glance at the underlying scores in the pop-up tooltip. 🔻 Allows alphabetical sorting

  • SNV/Indel - based on Base Quality, Depth, Mapping Quality, and Genotype Quality;

  • CNV - based on CNV Quality, Size, and Bin Count.

🔻 Allows alphabetical sorting

Protein Change - protein change (transcript-specific).

Splice Prediction - summarized in silico splicing prediction score. Tip: you can glance at the underlying scores in the pop-up tooltip.

Variant Details:

  • SNV/Indel: genomic coordinates, nucleotide change, and dbSNP identifier;

  • CNV: genomic coordinates and size.

🔻 Allows sorting by genomic start location

Multiselection of variants and bulk actions (34.0+)

Multiselection of variants:

  1. Hover over a variant to reveal a checkbox at the start of the line;

  2. Checking the box exposes the Multiselect actions bar which replaces the Search bar, and checkboxes appear for all variants in the current view;

  3. Manually select variants one by one or check the Select all checkbox. Note: the Select all function applies solely to variants displayed on the current page, not all variants matching the active filters.


Bulk actions:

1. View/un-view variants

  1. In the Multiselect actions bar, click on the Viewed icon and select Viewed or Un-viewed. Note: user-tagged variants can’t be un-viewed.

2. Assign/remove tags

How to assign a tag to multiple variants at once:

  1. In the Multiselect actions bar, click on the Tag icon and choose a tag from the dropdown menu. Note: If any variants already possess tags, a warning message will appear. Click on Apply to proceed.

How to remove tags from multiple variants at once:

  1. In the Multiselect actions bar, click on the Tag icon, then click on:

3. Assign/clear pathogenicity

How to assign pathogenicity to multiple variants at once:

  1. In the Multiselect actions bar, click on the Pathogenicity icon and choose a pathogenicity class from the dropdown menu. Note: only tagged variants can have pathogenicity assigned.

How to clear pathogenicity from multiple variants at once:

  1. In the Multiselect actions bar, click on the Pathogenicity icon, then click on Clear.

Filters/Presets panel

The Emedgene Workbench offers a wide array of dynamic filters to help reveal or limit variants that are the most relevant to your clinical case. Each filter contains multiple options to customize the case review process according to your organization's best practices.

The Filters/Presets panel includes two tabs:

Download variants

Note: If your current selection comprises more than 1500 variants, only the first 1500 variants will be downloaded.

The file includes the following columns:
  1. Case id,

  2. Chromosome,

  3. Position,

  4. REF,

  5. ALT,

  6. END,

  7. Vartype,

  8. Gene,

  9. Transcript,

  10. Effect,

  11. Quality,

  12. Depth,

  13. Alternate Read,

  14. Proband Zygosity (called Zygosity before 34.0),

  15. GnomAD AF,

  16. GnomAD AC,

  17. GnomAD SV AF,

  18. GnomAD SV AC,

  19. Max AF,

  20. Pathogenicity,

  21. Coding Change,

  22. Protein Change,

  23. Hom,

  24. Hemi,

  25. Tag,

  26. Prediction,

  27. SpliceAI DS AG,

  28. SpliceAI DS AL,

  29. SpliceAI DS DG,

  30. SpliceAI DS DL,

  31. pLI,

  32. Missense z-score,

  33. pRec,

  34. Known Variants,

  35. Other Family Members,

  36. Mother Zygosity (34.0+),

  37. Father Zygosity (34.0+),

  38. Allele Bias,

  39. Reference,

  40. Evidence Text,

  41. Diseases (34.0+),

  42. Disease Inheritance Mode (34.0+),

  43. SIFT Pred (34.0+),

  44. LRT Pred (34.0+),

  45. MutationTaster Pred (34.0+),

  46. Polyphen2 HVAR Pred (34.0+),

  47. Polyphen2 HDIV Pred (34.0+),

  48. DANN Score (34.0+),

  49. REVEL Score (34.0+),

  50. PrimateAI3D Score (34.0+),

  51. PrimateAI3D Prediction (34.0+),

  52. Variant inheritance (34.0+)

Analysis tools tab

The Analysis tools tab contains multiple tools that facilitate a case review:

Manually add variants to a delivered case

When you:

  • Complement NGS with other genetic tests done on the side (long-read sequencing, optical mapping, CGH, SNP array, karyotyping/FISH, repeat-primed PCR, MLPA, Southern blot, etc), or

  • Choose to report a few adjacent variants as a single multi-nucleotide variant,

the need to add variants on top of the analysis results arises.

You can manually add variants absent from the VCF or not called from the FASTQ. Supported variant types are SNV, CNV, UPD, ROH, and STR. SV is coming soon!


To manually add a variant:

  1. In the Manually Add Variant window select variant type among SNV, CNV, UPD, ROH, and STR.

  2. Fill in variant details according to the selected variant type:

  • Chromosome,

  • Position,

  • REF,

  • ALT,

  • Zygosity

  • Chromosome,

  • Position Start,

  • Position End,

  • REF,

  • ALT,

  • Type:

    • CNV: DEL, DUP,

    • UPD: IUPDMAT (maternal isodisomy), IUPDPAT (paternal isodisomy), HUPDPAT (paternal heterodisomy), HUPDMAT (maternal heterodisomy),

  • Zygosity

  • Chromosome,

  • Position,

  • REF Repeats Number,

  • ALT Repeats Number,

  • Repeats Unit,

  • Zygosity

  1. Click on Create Variant.


Manually added variant's Variant page


To filter by manually added variants:

Variant Type Filters

The Variant Type Filters allow filtering variant list by variant type:

  • Sequence variants: SNV, Indel (Note: Indel filter requires pipeline version 5.22.8 or higher);

  • CNV: DEL, DUP;

  • mtDNA SNV/Indel.

Variant Effect Filters

The Variant Effect Filters allow filtering variants by consequence, ACMG pathogenicity classes, and whether/how the variant has been classified internally or in clinical variation databases. The filters can operate in a Simple or Advanced mode.


Modes

Simple

Filter variant list by:

  • Severity of variant effect (High, Moderate, Low, Modifier);

  • CNV Severity is set according to the image below;

  • Known Variant (Known Variants, Known Pathogenic Variants) - variant status in clinical variation databases (ClinVar) and previous classifications by your organization or network.

Advanced

Further restrict analysis results by:

  • Specific Main effect of the variant on protein structure and function;

  • ACMG Classification (Pathogenic, Likely Pathogenic, Uncertain Significance, Likely Benign, Benign)- ACMG pathogenicity class assigned manually or automatically. Note: applicable only for Candidate and Most Likely variants;

  • ClinVar Known Variants (Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign, Other) - variant status in ClinVar;

  • Custom database Known Variants (Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign, Other) - variant status in your own curated variant database, including CNVs detected by means of NGS and/or chromosomal microarray;

  • Manually Classified Variants - select this option to restrict results to variants from previous cases with user-assigned Pathogenicity.


Default values

When Filters are Reset to Default, the Variant Filters are set to:

  • Severity: High, Moderate, Low;

  • Known Variant - no filtering.

Quality Filters

The Quality Filters allow one to filter variants by variant quality metrics. The filter can operate in a Simple or Advanced mode.


Modes

Simple

Select a minimum degree of sequencing Quality (Low, Moderate, High).

Advanced

For SNVs and Indels:

  • Select a minimum degree of sequencing Quality (Low, Moderate, High),

  • Define minimum Mapping Quality (0-60 - value can be exceeded using the text box),

  • Specify minimum Depth (0-500 - value can be exceeded using the text box),

  • Set minimum number of alternate reads in Alternate Read (0-500 - value can be exceeded using the text box). Note: available for cases run with pipeline version 5.26+.

  • Set limits on Allele bias (0-100). Note: when applied to mtDNA variants, the Allele bias filter operates on heteroplasmy levels.

For CNVs:

  • Set limits on CNV Length (50bp, 1kb, 10kb, 100kb, 1Mb, 100Mb, Max CNV length),

  • Set minimum CNV Bin Count (1, 5, 10, 25, 50, 100, 500).


Default values

  • Quality: Moderate and High,

  • Mapping Quality ≥45,

  • Depth ≥ 10,

  • Alternate Read - no filtering,

  • Allele bias - no filtering,

  • CNV Length - no filtering,

  • CNV Bin Count - no filtering.

As of version 2.26:

Filters

Variants can be filtered by:

Note: Quality, Polymorphism, and Variant filters can operate in either a Simple or Advanced mode.


In the Filters tab of the Filters/Presets panel, the vertical ellipsis button offers options:

  • Clear - deselect all filters and reveal all the variants;

  • Reset to Default - set default filters values: moderate/high quality (Quality Filter), low/moderate/high severity (Variant Filters), and Het/Hom zygosity in the proband (Zygosity Filters);

Preset groups

The combination of Presets is referred to as a Preset group.


Select a Preset group to display in the case


Where can I manage Preset groups? (34.0+)

Disease - the number of disease associations and corresponding mode(s) of inheritance derived from and , and the name of one of the diseases are listed.

Father Quality - overall score in father:

Father Zygosity - variant in father. 🔻 Allows alphabetical sorting

gnomAD All AF - overall alternative allele frequency across gnomAD populations (also called Total AF in the ). 🔻 Allows numerical sorting

Main Effect - of the variant on protein structure and function (transcript-specific). By default the most severe effect is presented. 🔻 Allows alphabetical sorting

Max AF - the highest alternative allele frequency among all public population databases. Note: not to be confused with Max AF in that only considers gnomAD statistics. 🔻 Allows numerical sorting

Mother Quality - overall score in mother:

Mother Zygosity - variant in mother. 🔻 Allows alphabetical sorting

Pathogenicity - variant pathogenicity that has been manually assigned in the .

Proband Quality - overall score in proband:

Proband Zygosity - variant in the proband. 🔻 Allows alphabetical sorting

Tag - assigned by Emedgene or selected by a user.

Variant Notes - indicates if the variant has notes.

Note: multiselection and bulk actions are only available in non- cases to maintain data integrity and preserve the finalized case data.

How to change the for multiple variants at once:

variants of interest;

variants of interest;

variants of interest;

to remove user-assigned tags, or

to remove tags assigned by Emedgene's algorithm.

variants of interest;

variants of interest;

: Manually adjustable variant specifications;

: These are filter combinations that are custom-built and implemented according to the case analysis SOPs used by your team.

To do this, click on the Export icon on top of the .

- includes numerous adjustable Filters and Presets (on the left)

- a user-customizable display of all the analysis results (core section)

- when selecting a variant, the variant page opens, revealing a detailed annotation and other assessment tools for the particular variant.

Click on the plus button on the top right of the .

Note: if you do not see this option, please and we will provide you with the relevant .

Unlike regular variants, the manually added variant's has a blue frame and a "Manually added variant" title.

Note: and sections of the Variant page are not relevant for manually added variants, and section is not available for now. Automatic assignment of ACMG criteria is not available for manually added variants but you may manually select the relevant tags and the final variant class will be calculated on the fly.

In select Manually added variants:

When are Reset to Default, The Quality Filters are set to:

: Variant quality metrics

: Alternative allele frequencies and genotype counts in public and internal databases

and : Variant consequences, ACMG pathogenicity classes, variant types (sequence, structural, mtDNA), and whether and how the variant is classified in clinical variation databases.

: Disease-associated genes, genes of unknown significance, ACMG clinically actionable genes, cancer-associated genes, candidate gene list, etc.

: Gene-disease associations that match the proband's clinical phenotypes

: Select a mode of inheritance that is compatible with the genotypes and phenotypes of affected and healthy family members

: Filter by genotypes in selected samples

: Variants tagged by the user or the AI Shortlist, manually added variants, and other organization level filters.

🆕 34.0+: Save as preset - create a new based on the currently active filters. ​

You can implement different combinations of to be used for different case types (i.e. Presets for exome may be different from Presets for genome) as defined by your SOPs to further streamline case review.

Preset group selection is available in the Case info screen of the flow while or a case.

To manage filter Preset groups, navigate to > > :

From here, you can create ( /, , and Preset groups as needed.

Here, you can set a Preset group as default, so it will be used unless another Preset group is selected during .

OMIM
CGD
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Summary section
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Summary section
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Evidence section
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variant tag
Variant Interpretation
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Quality
Visualization
Population Statistics
User filters
Filters
Quality Filters
Polymorphism Filters
Variant Type Filters
Variant Effect Filters
Gene Filters
Phenomatch Filters
Inheritance Filters
Zygosity Filters
User Filters
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Default Preset group
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Presets

For versions prior to 34.0, technical support is required to implement a customized filter Preset. But with version 34.0 and later, users can easily do it on their own.


Create filter Presets from active filters (34.0+)

To save Presets from active filters:

  1. Click on the three-dot icon;

  2. Select Save as preset;

  3. Enter a name for the Preset (Note: Avoid using non-Latin symbols that don't follow the ISO-5589-1 standard);

  4. Click Save.


Where can I manage Presets? (34.0+)


  1. In Presets, scroll down and click Add beside Gene Lists.

  1. Select the gene lists you want to utilize as filter presets by marking the relevant checkboxes. Starting from version 30.0+, a search bar simplifies list navigation by allowing you to search by list name.

  1. Click Save.

Presets originating from gene lists will appear in Presets under Gene Lists.


Review logic behind the Preset (32.0+)

On 32.0+, for a quick refresher, you may review the logic behind each Preset directly within your analysis flow. To do so, click on an downward arrow icon left to the Preset's name.

Not relevant

Presets are combinations of that match your case analysis SOPs.

Open the panel and navigate to the tab;

To manage filter Presets, navigate to > > > . From here, you can , , or the preset as needed.

Create filter Presets from your (32.0+)

Filters
Filters
Filters
Settings
Organization Settings
Lab Workflow
Presets
edit
delete
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gene lists

Zygosity Filters

The Zygosity Filters enable manual selection of zygosity status (Het, Hom, Ref, No Cov) for each sequenced sample in the pedigree.

Polymorphism Filters

The Polymorphism Filters enable filtering variants by alternative allele frequencies and genotype counts in public and internal databases. The filters can operate in a Simple or Advanced mode.


Modes

Simple mode

Switch on or off Display Polymorphism option:

  • When switched on, no restrictions are being applied.

  • When switched off, variants with allele frequency >0.05 in public databases or >0.25 in the EmedgeneDB are filtered out.

Advanced mode

Filter variant list by limiting the maximum Allele Frequency, Hom/Hemi and Het counts in one of the public database options (GnomAD, ExAC, 1000 Genomes, or GME) or, by default, in all (All Databases). The default values for Hom/Hemi and Het can be exceeded using the text box.

In addition, limit results by the maximum Allele Frequency in internal databases:

  • Emedgene Database - a static sample set of 806 healthy individuals. Aimed at getting rid of the artifacts generated by our FASTQ processing pipeline

  • Organization Databases, e.g., NoiseDB - a blacklist of variants (implemented by request).


Default values

Inheritance Filters

The Inheritance Filters allow filtering variants using an assumed inheritance mode that is consistent with the segregation of genotypes and phenotypes in the family.

You can filter for:

  • Autosomal Recessive - Homozygotes. Autosomal variants that are Hom in the Proband and other affected family members (if any) and Het, Ref, or No Cov in the unaffected members.

  • Autosomal Recessive - Compound Heterozygotes. Two or more autosomal Het variants in the same gene inherited from different parents.

  • X-Linked Recessive. X-chromosome variants in a male Proband (i.e. Hemi) that are Het in his unaffected mother.

  • X-Linked Dominant. X-chromosome variants that are Het in affected females in the pedigree.

  • De Novo Dominant. Autosomal and X-chromosome variants that are Het in the Proband and Ref in parents.

  • Autosomal Dominant. Autosomal variants that are Het in the Proband and other affected family members but Ref in healthy relatives. ​

With the Display No Coverage slider, you can control whether to include or exclude variants that are No Cov in Proband or any other sequenced sample in that pedigree.

Phenomatch Filters

The Phenomatch Filters highlight variants located in the genes whose phenotypic annotation matches the proband's clinical presentation.

When one of the Phenomatch Filters is active, the results are limited to the variants that are top-rated by the corresponding algorithm:

  • Phenomatch - High Specificity – strictly filters genes with disease phenotypes matching the exact patient HPO phenotypes.

  • Phenomatch - Powered by AI – filters genes with disease phenotypes loosely matching the patient HPO phenotypes.

  • Phenomatch with Unknown – filters genes of unknown significance based on indirect links to patient phenotypes (including mouse models, gene families, pathways, etc.).

Gene Filters

The Gene Filters allow filtering variants by genes or specific regions:

  • All Disease Associated Genes - variants in the genes with a published disease association;

  • All Unknown Genes - variants in the genes of unknown clinical significance;

  • Candidate Genes - variants in a Gene list if defined during case creation;

  • All ACMG genes - variants in the clinically actionable genes defined by the ACMG:

  • Cancer Associated Genes - variants in genes with published association with oncological disease;

  • LoF Genes (Emedgene Knowledgebase 26+) - variants in extremely LoF intolerant genes (gnomAD pLI ≥ 0.9). Note: if a variant is a CNV that overlaps more than one gene, it will appear in the filtering results if at least one of the genes has gnomAD pLI ≥ 0.9);

  • Established HI/TS Genes (Emedgene Knowledgebase 26+) - variants in genes with sufficient evidence of dosage sensitivity (defined by having ClinGen's Haploinsufficiency and/or Triplosensitivity scores of 3);

  • Coding regions - variants restricted to the protein-coding sequences.


Default values

When are Reset to Default, The Polymorphism Filters are set to the Display Polymorphism option of the Simple mode, i.e., no filtering.

The Inheritance Filters are primarily relevant for cases with sequencing data for a trio pedigree and less relevant for singletons. For large and complex pedigrees, consider using that are more flexible.

(30.0+) - the latest and most refined phenotypic matching model based on Phenomatch - Powered by AI.

Versions 30.0+: 81 genes ();

Versions <30.0: 78 genes ().

In Targeted Regions - variants in the regions defined by the Enrichment Kit selected while .RefSeq coding regions will be used as a reference if no kit is provided.

When are Reset to Default, the Gene Filters remain disabled, except for cases launched in Virtual panel mode of the Gene list. In such a case, the Candidate Genes filter is activated by default.

Filters
Zygosity filters
Phenomeld
Miller et al. 2023
Miller et al. 2022
creating a case
Filters

User Filters

The User Filters allow filtering by variant tags assigned by the user or AI Shortlist:

  • Most Likely – variants tagged as Most Likely by AI Shortlist or by the user.

  • Candidates – variants tagged as Candidate by AI Shortlist or by the user.

  • Incidental – variants tagged as Incidental by AI Shortlist or by the user.

  • Carrier – variants tagged as Carrier by AI Shortlist or by the user.

  • Not Relevant – variants manually tagged as Not Relevant.

  • My Tags – variants tagged by the current user.

  • AI Shortlist (Auto Analysis) - variants tagged by the AI Shortlist.

With Notes – variants that are accompanied by . This filter returns all the automatically and manually variants, except those with manually removed Variant Interpretation notes (if any).

Submitted for Sanger confirmation – variants manually assigned as eligible for Sanger sequencing in the Variant page's .

- variants added manually on top of the analysis results.

With Pathogenicity Tag – variants with Pathogenicity manually assigned in the Variant page's .

Variant Interpretation
notes
tagged
Evidence section
Manually added variants
Evidence section

Phenotypic match strength


Phenotypic match strength levels:

Exact match

Same term as in the clinical synopsis of the suspected disease

Match by ascendance

Phenotypes share a parent term in the HPO hierarchy

Indirect match

Phenotypes are closely related in the HPO hierarchy, but term relatedness is lower than in Match by ascendance

Unmatch

The phenotype is not reported for the suspected disease.


Lab tab

The Lab tab displays sample quality in the following sections:

Summary dashboard

highlights the key sample quality indicators, with more details provided in the subsequent sections.

Sequencing lab information

reports sequencing run technicalities as indicated during case creation:

  • Lab

  • Instrument

  • Reagents

  • Kit type

  • Expected coverage

  • Protocol

Case quality (34.0+)

provides a broad overview of the case quality:

Chromosome validation

Ensures each chromosome has a minimum of one variant with high quality.

Note: Applies only to chromosomes with at least 100 SNV variants within defined Kit or coding regions.

GnomAD validation

Ensures each chromosome has a minimum of one variant annotated with GnomAD.

Note: Applies only to chromosomes with at least 100 SNV variants within defined Kit or coding regions.

  1. ClinVar validation

Ensures each chromosome has a minimum of one variant annotated with ClinVar.

Note: Applies only to chromosomes with at least 100 SNV variants within defined Kit or coding regions.

Auto analysis validation

Ensures at least one variant has been tagged by the AI Shortlist.

Note: Not applicable for cases with a gene list below the gene list threshold. The default threshold is set to 50 genes.

mtDNA reference validation

Sample quality

highlights metrics for each sample:

Quality

Overall sample quality indicator based on the average depth of coverage for the indicated kit (or RefSeq coding regions if no kit is provided), percentage of bases covered >20x, error rate, percentage of reads mapped to the reference sequence, and presence of contamination.

Sex validation results

Sex validation (called "gender validation" in versions before 33.0) is performed by comparing the observed homozygous/heterozygous genotype ratio on the X chromosome with the expected ratios for females (<2) and males (>2). Only high-quality Single Nucleotide Variants (SNVs) in the targeted regions specified by the kit (or RefSeq coding regions if no kit is provided) are considered. It is crucial to note that a minimum of 50 variants is required for accurate sex validation. Importantly, if we lack 50 high-quality SNVs, sex validation would not be performed, resulting in an "empty" return. For sample where sex was designated as "unknown" during case creation, the sex validation will present the "predicted" sex.

Ploidy estimation results (32.0+)

Specific quality parameters

Average coverage, bases with coverage >20x, error rate, % mapped reads, etc. Blue bars represent each of these parameters per sample, while a vertical line represents a general metric across all the samples across all the cases in the account.

Detailed QC metrics can be downloaded upon clicking on the download icon next to the section title.

Pedigree

For each possible pair of samples in a pedigree, the declared family relation is compared with the observed relatedness coefficient. The relatedness coefficient is calculated from the percentage of shared alleles and the size of the Identity By Descent blocks. IBS0 indicates the number of sites lacking shared alleles. This metric can help differentiate between sibling-sibling and parent-child relationships when both are expected to have ~50% relatedness.

When the relatedness coefficient for a parent-child pair or a full sibling pair falls outside the range of 40 to 60%, the relatedness check is considered failed.

If the relatedness coefficient indicates a very low chance of shared ancestry, it is classified as 'Shared Ancestry' (0.2%-4%). For relatedness coefficients that suggest closer genetic ties, it results in 'Consanguinity' (4%-15%). When the genetic similarity reaches a high threshold (>15%), it not only results in 'Consanguinity' but also triggers a warning/ 'Failed' quality.

Genes with insufficient coverage

Here, you can directly check if your genes of interest have been entirely covered. Consider using Sanger sequencing to cover gaps in the genes of interest.

Note: this feature is available only for FASTQ files.

To examine if the gene contains regions with insufficient coverage:

  1. Enter a gene symbol in the search box and select it from the dropdown.

  2. From the Coverage dropdown menu, choose between ≤0x, ≤5x, ≤10x, ≤20x, and ≤All.

  3. You can Download insufficient regions or explore them in the table. Pressing the More details button will open a pop-up window specifying the genomic coordinates of the poorly covered regions.

Simply click the Add Gene List button and select any of your pre-loaded gene lists.

You may further filter regions

by the maximal depth of coverage and the maximal percentage of bases covered greater than 20x.

  1. Click on More details:

  1. In the pop-up window click on View on IGV:

On the , each proband's phenotype is marked according to the degree of similarity to the phenotypes observed in the genetic condition presumably associated with a variant under review.

Each phenotypic match strength level is denoted by a particular icon next to the HPO term in the Case info tab of the :

Ensures that the mtDNA reference used was .

The DRAGEN Ploidy Estimator detects aneuploidies and determines the sex karyotype in whole genome samples. When the customer hovers their mouse over 'Failed,' they can view the problematic Chromosomes. It's worth mentioning that the 'Failed' notification appears when any of the autosomal median scores are below 0.9 or above 1.1. Learn more about the algorithm in the DRAGEN™ Bio-IT Platform .

Displays the results of the relatedness check by .

You may look up the coverage for multiple genes that are saved as a :

There is a link to the desktop browser for poorly covered regions:

Evidence page
Case details panel
rCRS
documentation
Peddy
Gene list
IGV

Clinical Report

With Emedgene's reporting solution, creating comprehensive Clinical Reports is a piece of cake.✨ All the relevant case- and variant-level information is automatically populated to the corresponding sections of the report.

Note: Emedgene offers the capability of customizing Clinical Reports upon request. We tailor Report templates for any use case according to your SOPs and aesthetic sense.


Exemplary Clinical Report layout and information sources

Case Information

  1. Patient details: Patient's name [1], date of birth [2], sex [2] and MRN [1];

  2. Technical sample details: Specimen's type [1] and quality [3], dates collected [1] and received [1];

  3. Provider details: Lab number [1], ordering physician's name [1];

  4. Report date [3];

  5. Case type [2];

  6. Clinical information: Indication for testing [2] or, if it's not available, Proband's phenotypes [2]; Secondary findings requested [2]: Yes/No.

Results summary

Results summary gives a general overview of the test result:

  1. Test result summary [4];

  2. Secondary ACMG findings summary [4];

  3. Interpretation summary [4];

  4. Recommendations [4].

Detailed results

Detailed results highlight the genetic testing findings:

  1. Basic sequence variant details:

    1. Gene [3],

    2. Genomic location [3],

    3. Zygosity/Inheritance [3] (Zygosity in Proband and their relatives),

    4. Classification [6] (Pathogenicity),

    5. Condition [7] (Disease and Inheritance mode if available).

  2. Basic copy number variant details:

    1. Chromosome region [3],

    2. Type: DEL/DUP [3],

    3. Genes [3],

    4. Zygosity/Inheritance [3] (Zygosity in Proband and their relatives),

    5. Minimum length [3],

    6. Classification [6] (Pathogenicity).

  3. Individual sequence variant interpretations:

    1. Basic variant details [3]: gene, genomic location, coding sequence and protein sequence change HGVS notations, exon involved, variant's main effect, Prediction, Conservation and Splice Prediction scores, gnomAD population statistics,

    2. Associated diseases [3] - all the diseases known to be associated with the gene,

    3. Quality [3]: Zygosity, base quality, depth in Proband and their relatives,

    4. Summary [8].

  4. Individual copy number variant interpretations:

    1. Chromosome region [3],

    2. Type: DEL/DUP [3],

    3. Minimum length [3],

    4. Zygosity in Proband [3],

    5. Classification [6] (Pathogenicity),

    6. Summary [8].

  5. Gene interpretation [4]

Test details

Test details:

  1. Test methodology [5];

  2. Test limitations [5].

References

The References [9] section lists all the PubMed citations mentioned in the report. References will be auto-formatted if the PMID is supplied in the report.

Signatures

The Signatures section documents who and when generated the report [3].


Generating a Clinical Report

You can download the report preview in a .pdf or .odt format.

You can download the report in a .pdf or .odt format.


Data sources

[1] - API;

[3] - automatically inferred by Emedgene,

[5] - fixed text,

[9] - in any of the free text fields you can add PMIDs in one of the following formats: PMID1234, PMID 1234, PMID:1234.

Versions tab

The Versions tab reports versions of all the tools and resources used during the case analysis in the following categories:

  • Annotation

  • Emedgene Resources

  • Knowledgebase Sources

  • Organization Local Databases

  • Population Databases

  • Variant Databases

Note: These versions remain static from the time a case is run. They are not updated unless a case is reanalyzed.

​

Includes (numbers indicate ):

Variant [3] (HGVS description relative to the transcript selected as a reference in the of the ),

After you completed the , you may want to have a look at the Report Preview before finalizing a case. To do this, click on the eye button located rightmost on the , select a template and click Preview.

After you changed to Finalized, you can Generate Report. All the generated reports are saved per case. Click on the printer button on the , select Create New or choose a previously generated report (if any), then select a template and click Generate.

[2] - filled in while ; displayed in ; for non-finalized cases;

[4] - filled in in the Case Interpretation widget while ,

[6] - manually assigned in the Pathogenicity box of the of the Variant Page,

[7] - depends on the evidence generated on the ,

[8] - automatically or manually filled in in the Variant Interpretation notes of the of the Variant Page,

Clinical Significance
section
Variant Page
Case interpretation
flow
Individual case page Top bar
Case status
Individual case page Top bar
adding a new case
Case Info
editable
finalizing the case
Evidence
section
Evidence page
Evidence
section
data sources

Variant zygosity notations

Hom = Homozygous for alternative allele;

Het = Heterozygous;

Hemi = Hemizygous (X-chromosome variants in males except for heterozygous variants in pseudoautosomal regions);

Ref = Homozygous for reference allele;

No Cov = Genotype unknown.

Evidence page

The Evidence page presents the most relevant evidence behind the automatic variant classification suggested by the AI Shortlist.


The Evidence page is accessible from:

Click on the variant bar.


View modes

You can switch between the graph and text view by clicking on the link on top of the page (Show evidence graph or Show evidence as text, respectively). The graph view is helpful for exploring the data, while the text view is relevant for collecting notes.

AI Shortlist collects data from credible studies and public databases in an internal knowledge base that maps complex connections between variants, genes, mechanisms, diseases, and phenotypes.


The Evidence page provides concise evidence for the specific variant, including:

Variant information

The main effect of the variant, its HGVS nomenclature for coding DNA and protein changes, and zygosity, including if the variant is de novo.

Gene information

Gene symbol, if the gene is tolerant to variation, and assumed inheritance mode in the case under review. This is suggested based on the observed level of genotype-phenotype co-segregation and inheritance mode of the genetic condition (reported or suspected).

In addition to the conventional inheritance modes (Autosomal Dominant, Autosomal Recessive, Compound Heterozygote Autosomal Recessive, X-Linked Dominant, X-Linked Recessive), the platform also employs Autosomal Dominant Partial Penetrance and Partial Autosomal Recessive designations.

Autosomal Dominant Partial Penetrance is used when the gene-associated condition is AD, and the variant is Het in the test subject and at least one of their parents. This suggests that the phenotypes may be due to incomplete penetrance of the genetic condition.

Partial Autosomal Recessive is used when the gene-associated condition is AR and the variant in the test subject is Het. This helps to account for the possibility that another causative variant is undetected - in the same (compound heterozygosity) or another (digenic inheritance) gene.

Disease information

Condition name as suggested by OMIM, other disease databases or in the literature.

Patient Phenotypes

Proband's phenotypes that match phenotypes reported for the suspected disease. Exact, indirect, and matches by ascendance are considered.

Unconfirmed Disease Phenotypes

Phenotypes reported for the suspected disease but not observed in the proband.

Unmatched Patient Phenotypes

Phenotypes observed in the proband but not known to be manifested as part of the suspected disease.


Links

Follow the links to the primary sources to explore the evidence further. The links are in the References section (text view) and are accessible by hovering over the arrows (graph view).


Edit mode

The evidence graph can be manually edited to include additional evidence for the case's resolution. To enter the edit mode, click on the pencil icon in the top left corner of the page. In this mode, you can edit, add, and delete text boxes.

Editing an existing case

If you would like to update or make corrections your case details, phenotypes or gene list, you have the option to edit the case and save or reanalyze the data.

How to edit case data:

  1. Press Edit case info button in the top right corner,

Note: When dealing with delivered cases, only specific data can be modified before initiating reanalysis:

Edits that won't affect the the AI Shortlist analysis, thus won't prompt reanalysis:

  1. Family tree screen:

    1. Clinical Notes,

    2. Patient Ethnicities,

    3. Suspected Disease Severity,

    4. Proband Suspected Disease Condition,

    5. Suspected Disease Penetrance.

  2. Case info screen:

    1. Indication for testing,

    2. Preset.

Edits that will affect the the AI Shortlist analysis, thus will trigger reanalysis:

  1. Family tree screen:

    1. Proband Phenotypes,

    2. Medical Condition.

  2. Case info screen:

    1. Genes list;

    2. Case Type.

⚠️ Any other modifications might result in reanalysis failure, so it's advisable to create a new case instead of modifying beyond these specified fields.

  1. After you've finished editing the case and pressed Next in the Case info screen, a window will pop up:

Select Reanalyze if you want to rerun the case.

Please find below a list of variant level evidences saved for variants tagged by the user during reanalysis:

  1. Tag value

  2. Variant interpretation notes

  3. Pathogenicity

  4. Selected transcript

  5. ACMG tags and notes

  6. Sanger and Sanger notes

In addition, at a case level, the checked Presets will be saved as well.

Select Save if you want to save changes without rerunning the case.

Keep in mind that if you've changed Proband phenotypes, results from Phenomatch filters still may change. A reminder that case data has been modified and prompt to launch reanalysis on the updated data will appear in the Case details panel on the right.

Finalizing a case

The finalized case status locks the case to prevent further changes to interpretation notes, ACMG tags, variant tags, pathogenicity and case-level interpretations.

How to finalize a case:

2. In the Case interpretation widget, indicate the final result of the analysis:

  1. Confidently Solved (Positive),

  2. Likely Solved (Positive),

  3. Further Investigation (Uncertain), or

  4. Unsolved (Negative).

Confidently Solved, Likely Solved, and Further Investigation end-result categories correspond to the Resolved case status supercategory.

Unsolved falls into the Not resolved status supercategory together with all the non-finalized cases.

The indicated case analysis outcomes are used to calculate the diagnostic yield.

You have the flexibility to reorder variants by drag-and-drop. The order of variants will be preserved in the Clinical Report within each variant table and/or section, defined by a variant tag and a variant type (e.g. SNVs tagged "In report").

Note: each variant in the Case interpretation widget is denoted at the coding DNA and protein level where applicable, otherwise, it's described at the genomic DNA level.

In Gene Interpretation, you can import gene annotation from Curate (30.0+).

5. To complete the Case interpretation flow, press Save.

You can download the report preview in a .pdf or .odt format.

All the generated reports are saved per case and each can be downloaded in a .pdf or .odt format.

Reflex genetic testing

You can expand to a broader genetic testing option if the results of more targeted testing are inconclusive. You may reflex from Custom Panel to Exome or Genome, or from Exome to Genome.

STR calling and interpretation

Calling methodology

Emedgene uses ExpansionHunter by DRAGEN to call short tandem repeats (STR), also known as repeats expansions.

STR calling with ExpansionHunter

Spanning reads

Exact sizes of short repeats are identified from spanning reads that completely contain the repeat sequence.

Flanking reads

When the repeat length is close to the read length, the size of the repeat is approximated from the flanking reads that partially overlap the repeat and one of the repeat flanks.

In-repeat reads (IRRs)

If the repeat is longer than the read length, its size is estimated from reads completely contained inside the repeat (in-repeat reads). In-repeat reads anchored by their mate to the repeat region are used to estimate the size of the repeat up to the fragment length. When there is no evidence of long repeats with the same repeat motif elsewhere in the genome, pairs of in-repeat reads can also be used to estimate the size of long (greater-than-fragment-length) repeats.

Note: ExpansionHunter for STR calling is designed for use in PCR-free WGS only. While STR variants might be called in exome cases, the limitations are currently unknown and it is therefore not recommended for use.

Recommendation for interpretation

In light of our recent experience and an internal investigation by the Illumina’s scientific team, we believe it is appropriate to enable prioritization for a subset of STR loci, but not all loci typed by DRAGEN. This is due to technical genotyping challenges and/or lack of scientific evidence of pathogenicity for the remaining loci. Current list of genes where STR may be tagged when appropriate is provided below:

Creating a case in Emedgene platform
Reading a case data from Emedgene platform
Example - connect integration1 workgroup as storage.

This view can be generated for any other variant after the variant has been manually .

Go to the and click on the See evidence button under the Evidence box.

Open a ,

You'll access the flow. You can edit any information on the Family tree screen, as well as Select genes list, Select preset, and Additional case info sections of the Case info screen.

The reanalysis will update the annotation with the latest ones available and rerun the AI Shortlist analysis. Since analysis output depends upon the data entered, we highly recommended rerunning the edited case. will change to Reanalysis.

Importantly, variant-level evidence from the first run is erased during reanalysis, EXCEPT for by or confirmed by the user.

1. On the , click on the Case interpretation button located on the top bar.

3. In the Case interpretation widget, select which tagged variants to include in the (if any). Variants are described at the genomic DNA level.

4. In the Case interpretation widget, you may add Interpretation notes, Gene interpretation, and Recommendations in the free-text format. This data is saved per case. If you’re using our customizable reporting solution, these fields will automatically populate in the .

6. If you're using Emedgene for reporting, you may want to have a look at the before finalizing a case. To do this, click on the eye button located rightmost on the , select a template and click Preview.

7. Change to Finalized.

Note: Finalizing a case will prevent users from making further changes to the case. To change information within the case (including and , Interpretation notes, Gene interpretation, and Recommendations, finalized variants, case analysis outcome, and , the case status must be changed from Finalized to another status.

8. To , click on the printer button on the , select Create New or choose a previously generated report (if any), then select a template and click Generate.

Note: for finalized cases, you can view the Case Result, Interpretation Notes and Finalized Variants in a new Finalize tab in the righthand panel of the case page. Another way to see the variants that were selected when the case was signed off is to select Finalized in the dropdown menu onthe .

To do this, you should change the Case type in flow, thereby rerunning using the broader analysis.

Thirty clinical genes associated with diseases caused by repeat expansion are called in and presented in the platform. Those genes are: AFF2, AR, ATN1, ATXN1, ATXN10, ATXN2, ATXN3, ATXN7, ATXN8OS, C9ORF72, CACNA1A, CBL, CNBP, CSTB, DIP2B, DMPK, FMR1, FXN, GIPC1, GLS, HTT, JPH3, NIPA1, NOP56, PABPN1, PHOX2B, PPP2R2B, RFC1, TBP, TCF4.

Gene
Associated Condition
Mode of Inheritance
Repeat Unit
tagged
Candidates tab
Variant page
Evidence section
case
Add new case
Case status
variants tagged
Individual case page
Clinical Report
Clinical Report
Report Preview
Individual case page Top bar
Case status
variant tags
Variant Interpretation
notes
Case Info
Generate Report
Individual case page Top bar
Candidates tab
Edit case info

ATXN10

Spinocerebellar ataxia 10 (SCA10)

Autosomal Dominant

ATTCT

ATXN8OS

Spinocerebellar ataxia 8 (SCA8)

Autosomal Dominant

CTG

ATN1

Dentatorubral-pallidoluysian atrophy (DRPLA)

Autosomal Dominant

CAG

ATXN1

Spinocerebellar ataxia 1 (SCA1)

Autosomal Dominant

CAG

ATXN2

Spinocerebellar ataxia 2 (SCA2)

Semi-dominant

CAG

ATXN3

Spinocerebellar ataxia 3 (SCA3)

Autosomal Dominant

CAG

ATXN7

Spinocerebellar ataxia 7 (SCA7)

Autosomal Dominant

CAG

CACNA1A

Spinocerebellar ataxia 6 (SCA6)

Autosomal Dominant

CAG

DMPK

Myotonic dystrophy 1 (DM1)

Autosomal Dominant

CTG

DMPK

Myotonic dystrophy 1, mild

Autosomal Dominant

CTG

FMR1

Fragile X tremor/ataxia syndrome (FXTAS) or Premature Ovarian Failure (POF)

X-linked

CGG

FMR1

Fragile X Syndrome (FXS)

X-linked

CGG

HTT

Huntington's disease (HD)

Autosomal Dominant

CAG

PPP2R2B

Spinocerebellar ataxia 12 (SCA12)

Autosomal Dominant

CAG

TBP

Spinocerebellar ataxia 17 (SCA17)

Autosomal Dominant

CAG

C9orf72

Amyotrophic lateral sclerosis and/or frontotemporal dementia (FTDALS1)

Autosomal Dominant

GGGGCC

AR

Spinal and bulbar muscular atrophy (SBMA)

X-linked

CAG

FXN

Friedreich ataxia (FRDA)

Autosomal Recessive

GAA

CNBP

Myotonic dystrophy 2 (DM2)

Autosomal Dominant

CCTG

JPH3

Huntington disease-like 2 (HDL2)

Autosomal Dominant

CTG

NOP56

Spinocerebellar ataxia 36 (SCA36)

Autosomal Dominant

GGCCTG

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Drawing
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DRAGEN version 3.9

Variant activity panel

The Variant activity panel on the righthand side of the Variant page records variant-level user activities, such as:

  • Adding comments,

  • Drafting Variant Interpretation notes,

  • Editing evidence graph, etc.

Desktop apps panel

The Desktop apps panel allows you to activate or inactivate connections with your IGV and Alamut desktop applications. This means there won't be any IGV and Alamut windows popping up unless you want them to!

Once you've configured your preferences for the desktop applications connections, they will be saved for your user account and applied to all cases.

Summary section

Each of the Summary section cards has a button linking to its original location on the Variant page where you can see more details and/or edit the evidence.

Let's look closer at each of the cards:

1) Variant Interpretation

2) Variant Info

  • Sequence variant (SNV/Indel), mtDNA variant (SNV/Indel): main effect*,* gene symbol, if available - HGVS descriptions on coding DNA and protein levels.

3) Quality

  • Sequence variant (SNV/Indel), mtDNA variant (SNV/Indel), STR:

    • variant caller (32.0+),

    • sample name,

    • zygosity,

    • depth of coverage,

    • percentage of alternative allele reads,

    • overall variant quality.

  • CNV (DEL/DUP):

    • variant caller (32.0+),

    • sample name,

    • zygosity,

    • overall variant quality.

4a) Population Summary

Population statistics from gnomAD (calculated for the combined gnomAD population including both exome and genome samples):

  • Total AF - overall alternative allele frequency,

  • Allele count - Counts of alternative allele (or Homoplasmy Count for mtDNA variants),

  • Hom/Hemi count - Counts of alternative allele in homozygous or hemizygous state (or Heteroplasmy Count for mtDNA variants),

  • Max AF - the highestalternative allele frequency among gnomAD populations;

Population statistics from organization databases (if available):

  • Allele count - Counts of alternative allele,

  • Hom/Hemi count - Counts of alternative allele in homozygous or hemizygous state.

4b) STR repeats distribution (2.28+)

STR repeats distribution displays allele counts in gnomAD and 1000 Genomes Project, as well as gnomAD pathogenicity ranges.

5) Gene's related diseases

  • Number of gene-disease connections for this gene within Emedgene knowledge base,

  • Disease name,

  • Disease inheritance mode,

  • Link to the gene-disease connection source(s),

6) Pathogenicity

Here you can see manually-assigned variant Pathogenicity, change it or select one from the dropdown if it's empty.

7) Clinical significance

Showcases ACMG tags assigned to the variant and the resulting classification.

  • Sequence variant (SNV/Indel), mtDNA variant (SNV/Indel)

    • 32.0+: the final class, the criteria used and the score.

  • CNV (DEL/DUP)

9) In silico Prediction

Overall estimations of in silico prediction results.

  • Small variant (SNV): Missense Prediction, Conservation, Splicing Prediction;

  • Small variant (Indel): Conservation;

  • mtDNA (SNV/Indel): Missense Prediction;

  • CNV (DEL/DUP), SV, STR: not available.

Variant page

Individual case page > Analysis tools tab > Variant table > Variant page

​Note: You can alternatively use arrows on either side of the Variant page window.

The Variant page is comprised of:

  1. Navigation panel (left). Divided into five tabs, leading to the corresponding page sections.

  2. Page body:

Variant page top bar

The Variant page top bar displays:

  1. Case ID,

  2. Gene symbol,

  3. Genomic location of the variant,

  4. Variant tag field.

V37 and below: If the variant is already in your Curate database, you will see an Open Curate button. Otherwise, you will see an Export to Curate button.

V38+: Clicking on this button will open a menu with 3 options:

  1. If the variant is not already in your Curate database, you will see an Add to Curate button. Clicking this button adds the variant to Curate for further review and editing.

  2. If the variant is already in your Curate database, and you have the “kms_export” role, you will see an Update in Curate button. Clicking this button updates the variant record in Curate with information from the current Analyze session, including:

    1. Pathogenicity

    2. Variant interpretation

    3. Gene-related disease (unless it is custom)

    4. Selected transcript (unless it is custom)

    5. ACMG data (classification, score, tags, tag strength, tag notes)

  3. If the variant is already in your Curate database you will also see an Open in Curate button.

Variant tagging widget

Any variant can be tagged by the AI Shortlist or a user as:

  • Most Likely Candidate - most promising for solving the case;

  • Candidate - worth considering;

  • Carrier - identified by the Carrier analysis pipeline;

  • In Report - manually selected to be reported;

  • Not relevant - automatically tagged variant that has been disregarded after manual review;

  • Any custom tag used in your organization (e.g., Submitted for Sanger confirmation).

Variant tagging widget how-to

Add or change a tag

Click on the dropdown icon in the Variant tag field and select a suitable tag. The Variant tag field showcases the most recently assigned tag.

Review the tagging history

  • 25.0.0+: click on the Variant tag field and scroll to the Assigned tags section.

  • 23.0.0 and older: click on the View all tags.

Remove an automatic tag

Click on the dropdown array in the Variant tag field and select Not relevant.

Clear your manual tag:

Click on the dropdown array in the Variant tag field and select Clear.

Note: you can't clear a tag added by another user.

CNV overlap percentage

Examples of CNV overlap percentage calculation (see legend below):

  • Orange represents the current CNV;

  • Violet blue represents a previously reported CNV;

  • Darker shade indicates the region of overlap between the current and previously reported CNV.

Related Cases section

Note: data is automatically lifted over between genome references on the fly.

The section features:

  1. Simple mode allows you to show or hide Network data altogether.

  1. Advanced mode gives you the flexibility to select specific networks to display.

  1. Green - Benign,

  2. Blue - Likely Benign,

  3. Light grey - VUS,

  4. Orange - Likely Pathogenic,

  5. Red - Pathogenic,

  6. Dark grey - N/A;

You can filter cases by Pathogenicity simply by clicking on the respective section of the percent bar. To clear filters, click on See all.

CNV variants: Dynamic CNV overlap percentage filter;

A table that summarizes details of previous variant interpretation.

Variant and case specifics are available with a single click on the corresponding row of the table (31.0+):

  • Proband ID,

  • proband phenotypes,

  • proband age,

  • proband sex,

  • maternal and paternal ethnicity,

  • case type.

The table comprises the following information:

  1. Collaborator (32.0+)

  1. Case status icon (32.0+)

  1. Lock icon(32.0+)

  1. Case ID (32.0+) or Case name (before 32.0)

  1. Variant Details (2.29+, CNV variants)

Displays variant coordinates in GRCh37 and GRCh38 genome references, along with the CNV length.

  1. Overlap (2.29+, CNV variants)

  1. Pathogenicity

  1. Date

Date of case creation.

  1. Tag

  1. Zygosity (30.0+) or Variant Inheritance (before 30.0)

  1. Link icon (32.0+)

  1. Letter icon (32.0+)

Population Statistics section

The Population Statistics section addresses detailed population allele data across various ethnicities in public and internal databases.

  • Public databases (SNVs): 1000 Genomes, ESP 6500, ExAC, and gnomAD

  • Public databases (CNVs): 1000 Genomes, gnomAD SV, Decipher, DGV

  • Internal databases: EmedgeneDB and organization's NoiseDB or other custom databases

By clicking on a particular row of the table, it will provide additional details including alternative allele frequency, alternative allele count, and homozygotes count reported for the selected population by different sources.

Population Statistics for mtDNA variants

The Population Statistics section displays population allele data across various ethnicities in:

  • Internal databases: EmedgeneDB and organization's NoiseDB or other custom databases

By clicking on a particular row of the table, it will provide additional details including the highest homoplasmy frequency, heteroplasmy count, homoplasmy count, and the total number of samples.

Quality section

The Quality section:

  1. Outlines the major variant quality parameters underlying the general grade in each sequenced individual:

  • SNV/Indel variants:

    • Base Quality,

    • Depth,

    • Mapping Quality,

  • CNVs:

    • Copy Number,

    • CNV Quality,

    • Size,

  • STRs:

    • Depth;

    • Repeat Number,

  1. Illustrates the allele fraction per sample in a pie chart. Not relevant for CNVs.

To change the sample in review for the particular variant, click on the corresponding icon in the family tree.

Clinical Significance section

The Clinical Significance section summarizes essential variant-level and gene-level information and indicates the gene's associated diseases.

This tab is comprised of five different blocks:

1. Variant Info

  1. Variant type,

  2. Main effect,

  3. Zygosity in each sequenced family member,

  4. Gene symbol and HGVS descriptions on coding DNA and protein levels. The transcript is marked:

    • with a tick - if it is canonical,

  1. Exon number and the total number of exons in the transcript chosen,

  2. Links to resources, such as UCSC genome browser, GeneCards, PubMed, WikiGenes,

  3. dbSNP ID and link (Note: SNV/Indel variants only),

  4. SV Type: DEL/DUP (Note: CNVs only),

  5. SV Length (Note: CNVs only),

  6. Link to DECIPHER (Note: CNVs only).

2. In silico Predictions

Standalone scores for Pathogenicity (Missense) Prediction, Conservation, and Splicing Prediction. These are the summarized indicators computed by our proprietary algorithm based on the in silico prediction tools' output. Click on the dropdown icon next to the score to see the individual scores.

Currently available in silico predictions per variant type:

Note: variants of types CNV, SV and STR are not annotated with in silico predictions.

3. Gene Metrics

from ExAC and gnomAD that resemble clinically relevant gene properties:

1. p(LoF intolerant)

pLI = p(LoF intolerant) is a probability of being loss-of-function intolerant to heterozygous and homozygous LoF variants.

Scale:

  • 🔴 pLI ≥ 0.9: extremely LoF intolerant,

  • 🟠 pLI > 0.1 & < 0.9: intermediate value,

  • 🟢 pLI ≤ 0.1: LoF tolerant.

2. Z missense

The Z missense score indicates intolerance to missense variants based on the deviation of observed missense variants versus the expected number.

Scale:

  • 🔴 Z missense ≥ 3: missense intolerant,

  • 🟠 Z missense > 2.5 & < 3: intermediate value,

  • 🟢 Z missense ≤ 2.5: missense tolerant.

3. p(REC)

p(REC) is a probability of being intolerant to homozygous, but not heterozygous LoF.

Scale:

  • 🔴 p(REC) ≥ 0.8: Hom LoF intolerant,

  • 🟠 p(REC) > 0.2 & < 0.8: intermediate value,

  • 🟢 p(REC) ≤ 0.2: Hom LoF tolerant.

4. RVIS ratio

RVIS = Residual Variation Intolerance Score is indicative of a gene's intolerance to functional variation based on comparing the overall number of observed variants in a gene to the observed common functional variants.

Scale:

  • 🔴 RVIS ≤ 30: functional variation intolerant,

  • 🟠 RVIS > 30 & < 50: intermediate value,

  • 🟢 RVIS ≥ 50: functional variation tolerant.

5. pLoF o/e

O/E Score is the ratio of the observed/expected number of LoF variants. It is a continuous measure of gene tolerance to LoF variation that incorporates a 90% confidence interval. The closer the O/E is to zero, the more likely the gene is LoF-constrained. If a hard threshold is needed for the interpretation of Mendelian disease cases, use the upper bound of the O/E confidence interval < 0.35.

Note: Gene Metrics are not available for CNVs or mtDNA variants.

4. Gene's related diseases

as reported in OMIM, ORPHANET, CGD, ClinVar, and academic papers included in the Emedgene's knowledge graph. Each of the entries is provided with an inheritance mode icon and a link to the source.

5. Clinical significance

highlights previous pathogenicity classifications of the variant under review:

  • Manually Classified indicates if the variant has been previously classified in any of the organization's cases by any user.

  • ClinVar provides a list of ClinVar submissions for the selected variant.

  • ClinGen Regions (only for CNVs) indicates whether a variant overlaps the established dosage-sensitive region defined by ClinGen.

  • Custom database shows a variant class from the variant database(s) curated by your organization. We can easily implement an organization's curated database of classified SNV or CNV variants to facilitate the case review.

a variant,

The Variant activity panel appears as a tab in the .

The Desktop apps panel appears as a tab in the sidebar.

The Summary section highlights core variant-related information from other sections:

(, , , ),

(),

(),

(, , ).

Notes added automatically or manually in the . Shown only if not empty.

* CNV (DEL/DUP): CNV length, variant type, number of genes involved, list of gene symbols. If the gene list is partial, you may hover over it to see the full list.

Number of patient's phenotypes matching disease phenotypes out of the total. Note: displayed by default for automatically tagged variants; for manually tagged variants you need to first trigger automatic generation of the evidence by entering the variant's .

This card highlights previous pathogenicity classifications in public and your private variant databases including . Each classification source is represented by one badge. Uncertain and Other classifications are only shown if there are no Benign/Likely Benign and/or Pathogenic/Likely Pathogenic classifications of this variant in a particular database.

8)

before 32.0: the final class and the criteria used.

The Variant page showcasing the comprehensive variant information is accessible from the by selecting the corresponding variant row with a click. Once you're on the Variant page, you can move between variants using left and right arrow keys of your keyboard.

. Displays Case ID, gene symbol, genomic DNA-level description of the variant, variant , and a link to your database. If the variant is already in your Curate database, you will see an Open Curate button. Otherwise, you will see an Export to Curate button.

. Highlights core variant-related information from other sections

. Reports essential variant- and gene-level information and indicates gene-related diseases.

. Outlines the major variant quality parameters in each sample and demonstrates the family tree with the zygosity for each sequenced sample.

. Features the IGV-based BAM file viewer.

. Addresses alternative allele frequency, alternative allele count, and the number of homozygotes in public and internal databases.

. Displays statistics regarding the pathogenicity and tags assigned to the variant under review, incorporating data from previous cases within both your organization and .

. Highlights user-selected variant pathogenicity, ACMG class (for a or a variant), and interpretation notes.

(right). Records variant-level user activities, such as a variant, adding comments or evidence notes, or editing the evidence graph. Variant activity panel pops up upon clicking the Activities button.

,

notes if available,

If the variant has been manually (besides or instead of automatic tagging by the AI Shortlist), the user-selected tag will be shown. Otherwise, you'll see an automatically selected tag or N/A for no tag. Clicking on the Variant tag field lets you review a record of tagging in a dropdown, in the Assigned tags section. The variant tag menu also includes Viewed by section. Note: After a case , all variants appear as not viewed.

A link to your database.

- found in one of the medically actionable genes defined by the ACMG;

Variant tags are shown in the Variant tagging widget of the . If the variant has been tagged manually (besides or instead of automatic tagging by the AI Shortlist), the user-selected tag will be shown in the Variant tag field. Otherwise, you'll see an automatically chosen tag or N/A for no tag.

The Variant page > section offers a as well as an column for CNVs in the data table. This percentage is computed by dividing the length of a common region between CNVs by the size of the CNV under study.

The Related Cases section highlights variants that appear in previously analyzed cases, both within your organization and among organizations in your .

data View mode switch (32.0+);

A percent bar that illustrates trends in previously attributed ;

The filter allows to manually adjust the lower limit of one-way annotation between the current CNV and CNVs that have been reported earlier by using a slider.

,

,

,

The organization from which the case originates. Either your organization or the collaborating organization that is part of your .

The lock icon is displayed for cases that have of .

Displays the and the reference genome used.

CNV percentage.

Variant's assigned in the previous case.

Previously assigned .

Variant in the proband and other case samples. Bold indicates an affected individual.

Available for cases from your organization. Upon clicking, the , filtered by the respective Case ID, will open in a new browser tab. Here you can check the .

Want to get in touch with a collaborator from your ? Simply click the letter icon, and their email address will be copied to your clipboard.

Public databases: gnomAD and

Demonstrates the family tree with zygosity status and the overall variant quality indicated for each sample. Zygosity (HET, HOM, HEMI, or REF) is marked inside the symbol, and variant quality grade (H, M, or L) is denoted on the side.

The variant quality score in the proband is highlighted in the section title. Upon 32.0+, the title also features variant caller notation.

Genotype Quality.

Bin Count.

Repeat Length.

with a Curate logo - if it has been selected in your database.

You may change the reference transcript by selecting one from the dropdown menu, or adding one not listed. For certain variants, such as upstream or downstream gene variants, HGVS descriptions may not be available. In these cases, you have the option to manually input coding change information. The notation should adhere to the format: GENE,NM_123456:c.-123N>N (no spaces are allowed). Once added, this information becomes available for the .\

SNV
Indel
mtDNA (SNV/indel)

Networks Classified indicates if the variant has been previously classified by the partnering organizations in your .

Caution: Please be aware that as of 32.0 there might be instances where the Variant page > Clinical significance > Networks classified section appears erroneously empty. However, you can still rely on the Variant page > , which will continue to display relevant information as intended. Please utilize the Variant page > Related cases section while the fix is being implemented.

indicates if the variant has been previously classified in your Curate variant database.

MITOMAP shows a variant's status in . By clicking on the MITOMAP interactive link, you will be taken to .

Tagging
Variant page sidebar
Variant page
Variant page
Evidence section
Evidence page
Curate
ACMG Classification
Variant table
Top bar
tags
Curate
Summary section
Clinical Significance section
Quality section
Visualization section
Population Statistics section
Related Cases section
networks
Evidence section
sequence
genomic
Variant activity panel
tagging
Variant Type
Variant Interpretation
tagged
reanalysis
Curate
Incidental
Variant page Top bar
Clinical Significance section
Variant Info
In silico Prediction
Gene's related diseases
Clinical significance
Quality section
Quality
Population Statistics section
Population Summary
Evidence section
Variant Interpretation
ACMG Classification
Pathogenicity

Pathogenicity (Missense) Prediction

+ Polyphen2 HDIV Polyphen2 HVAR SIFT MutationTaster LRT DANN REVEL PrimateAI-3D (34.0+)

-

+ APOGEE MitoTIP

Conservation

+ SiPhy 29 Mammals GERP RS phastCons 100 vertebrate

+

GERP RS

-

Splicing Prediction

+ dbscSNV-RF dbscSNV-Ada SpliceAI DS AG SpliceAI DS AL SpliceAI DS DG SpliceAI DS DL

-

-

Related Cases
Dynamic CNV overlap percentage filter
Overlap
tagged
network(s)
Network
Pathogenicity
overlap
Variant Interpretation
ACMG tags
selected disease
network
opted out
extended sharing
Case ID
annotation overlap
Pathogenicity
Variant tag
zygosity
Cases tab
Case details
network
MITOMAP
pedigree
Curate
report
network
Related cases
Curate
MITOMAP
MITOMAP: Reported Mitochondrial DNA Base Substitution Diseases: Coding and Control Region Point Mutations

Visualization section

Drag visualization tracks, set parameters on the right-hand side and zoom in or out to easily customize your view. To see more details, click on the track of interest.

Visualization tracks

Default tracks:

  1. FASTA track displays reference genome sequence;

  1. RefSeq Genes track displays gene(s) and transcript(s) affected by the variant;

  1. Protein domain track (37.0+) - Immediately under the RefSeq track we have added a Protein domain visualization track, using data from Uniprot GRCh38 with a liftover to GRCh37. Clicking a domain will display Name, start, end, ID and link out to UniProt. The track is available for cases created with knowledge graph 73+ versions.

  1. Test Subject VCF track (2.28+) represents proband's variants stored in the VCF file. It may come in handy when you're looking for MNVs or large CNVs that may overlap with other variants;

Additional tracks:

  1. BAM tracks for non-proband samples represent read alignment in patient's relatives;

  1. BigWig (2.29+)/ TNS (32.0+) track visualizes output of a systematic noise reducing pipeline - tangent normalized signal (TNS). The TNS track simplifies and increases reliability of CNV analysis. Note: On versions prior to 34.0, BigWig / TNS track is only available for WGS cases run from FASTQ.

  1. BAF (32.0+) track presents B-Allele Frequency. The track aids in CNV and LOH analysis. Note: On versions prior to 34.0, BAF track is only available for WES and WGS samples run from FASTQ.

  1. ROH (32.0+) track displays runs of homozygosity from whole genome calls on autosomal human chromosomes. The Regions of Homozygosity (ROH) plot is a visualization of homozygosity that may suggest the presence of uniparental isodisomy or partial isodisomy. Multiple ROH in an individual sample can indicate parental relatedness, which may be associated with an increased risk for a recessive disease. Note: On versions prior to 34.0, ROH track is only available for WGS cases run from FASTQ.

When hovering over the region, the ROH score, the number of homozygous SNVs, the number of heterozygous SNVs, and region's start and end positions are displayed.

​

Curated data tracks:

  1. ClinVar* track shows short variants submitted to ClinVar.

  1. ClinVarSV* track shows structural variants submitted to ClinVar.

*Colors indicate variant pathogenicity:

  1. Green = Benign/Likely Benign,

  2. Yellow = VUS,

  3. Red = Pathogenic/Likely Pathogenic,

  4. Black = Conflicting interpretation of pathogenicity;

  5. Grey = No assertion provided.


Variant Highlighting

To assist in identifying and tracking genomic variants, the platform highlights variant regions with a light blue overlay in all relevant tracks. The highlight remains visible when zooming or panning and dynamically moves to newly selected variants.


Reference Lines

To enhance clarity and facilitate a better understanding of genomic data, distinct reference lines are incorporated across various tracks, tailored to provide critical data points at a glance:

  • TNS Track:

    • Grey dashed line at Y=0.0

    • Red dashed line at Y=-0.5

    • Blue dashed line at Y=0.5

    • Y-axis fixed range from 2.0 to -2.0

  • BAF Track:

    • Grey dashed lines at Y=1.0, Y=0.5, and Y=0.0

    • Y-axis fixed range from 1.1 to -0.1

  • LogR (Array Only) Track:

    • Grey dashed line at Y=0.0

    • Red dashed line at Y=-0.5

    • Blue dashed line at Y=0.5

    • Y-axis fixed range from 2.0 to -2.0


Visualization section viewing modes (2.29+)

Simple viewing mode

By default, the Simple mode displays:

  1. RefSeq Genes track;

  2. Test Subject track;

  3. Test Subject VCF track (2.28+).

Additionally, you can select whether to show:

  1. Read alignment tracks for other case samples

(separate feature up to 2.28, part of Additional tracks in 2.29+);

  1. All Curated data tracks for all case samples (2.29+);

  1. All Additional tracks for all case samples (2.29+).

Advanced viewing mode

Logic behind ACMG classification of SNVs

ACMG score

The software computes the ACMG score for SNVs by assigning points to each active criterion based on the strength of evidence provided:

  • Supporting evidence: 1 point,

  • Moderate evidence: 2 points,

  • Strong evidence: 4 points,

  • Stand alone/very strong evidence: 8 points.

The total score is determined by summing the points from the pathogenic criteria checked, minus the sum of points from benign criteria. The score is interpreted according to the following thresholds:

  • Pathogenic: ≥ 10,

  • Likely Pathogenic: 6 to 9,

  • Uncertain Significance: 0 to 5,

  • Likely Benign: -6 to -1,

  • Benign: ≤ -7.

For mtDNA variants, the software excludes the following tags from the score calculation: PM1, PM3, PP2, PP5, BP1, BP3, and BP6.

​

ACMG classification

We implemented a technical automated solution for most criteria based on our scientific advisors’ recommendations and feedback from top clinical customers. For each criterion, we elaborate on the logic employed and the associated underlying thresholds. In addition, we give the user the flexibility to change the weight of specific criteria based on his professional judgment as recommended by ACMG/AMP guidelines.

For mtDNA variants, the software excludes the following tags from the score calculation: PM1, PM3, PP2, PP5, BP1, BP3, and BP6.

Importantly, we have made some adaptations of specific criteria (described below), and several criteria are not automatically calculated and require manual evaluation: PS4, PP4, BP5, BS1 and BS2.


PVS1: “Null variant in a gene where LOF is a known mechanism of disease.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. Variant must be “null variant”: We assess null variants as variants with high severity effect (i.e stop-gain, frameshift etc.). It should be noted that variants with a high splice prediction effect will be included in this tag independently of their main effect.

  2. LoF is a known mechanism of disease within the relevant gene: We are checking in ClinVar if there are any submissions of pathogenic or likely pathogenic variants with the following attributes: A review status with minimum 2 stars, LoF variant, variant within the related gene and size less than 51bp.


PS1: “Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. Variant must be a missense.

  2. The splicing prediction for the variant should not be High.

  3. A different missense ClinVar pathogenic/likely pathogenic variant (with 2-4 stars) has been previously described leading to the same amino acid change.

PS2: “De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. Variant is de novo variant: A de novo variant is defined as a variant with zygosity heterozygote (on autosome or on chromosome X for female) or HEMI (on chromosome X for male) for the proband and reference for the parents (parents have to be unaffected).

  2. The relatedness of the samples has been confirmed: As part of the lab validation service, we are checking the familial relatedness based on the genomic data.

PS3: “Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant was reported in ClinVar as Pathogenic or Likely Pathogenic with 2-4 stars.

  2. Supporting evidence from functional studies is available. For this, we are checking the publications associated with ClinVar submission and if any of them contain functional studies.

On the UI interface, the user also has the possibility to add a publication supporting a damaging effect on the gene or gene product.

PS4: “The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.”

This criterion is not currently automated, however the user can manually enter the corresponding information on the UI.


PM1: “Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant should be a missense variant.

  2. The variant should be in a Hotspot region: A Hotspot region is defined as a region of 30 bp surrounding the variant, where the number of missense pathogenic/likely pathogenic variants reported in ClinVar is greater than 70% of the total number of missense variants reported in ClinVar for this region.

  3. The Hotspot region should contain at least 10 missense variants reported in ClinVar.

Note: The tag isn't relevant for mtDNA variants and won't be automatically applied to them.

PM2: “Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, ExAC or Gnomad (not comprising Gnomad other) and Local database if >1000.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. For dominant disorders, the variant was not reported in any relevant population statistic database.

  2. For recessive disorders, the variant was reported with an allele frequency lower than 0.5 % and an hom/hemi count lower than 3 in any relevant population statistic database.

PM3: “For recessive disorders, detected in trans with a pathogenic variant.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The case must contain parental information.

  2. The variant must be compound heterozygote.

  3. The second variant (in trans) must be reported as pathogenic/likely pathogenic in ClinVar (with 2-4 stars).

  4. The disease inheritance mode must be recessive.

Note: The tag isn't relevant for mtDNA variants and won't be automatically applied to them.

PM4: “Protein length changes as a result of in-frame deletions/insertions (in a non-repeat region) and stop losses.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant is an in-frame insertion or deletion variant.

  2. The variant is not within a repeat region. The repeat regions used are the ones as defined by Repeat masker data from UCSC.

OR 3. The variant is a stop lost.

PM5: “Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. Variant must be a missense variant.

  2. This variant or a different missense pathogenic/likely pathogenic variant has been previously described in ClinVar at the same amino acid position. Please note, we modified this condition to take into consideration the described variant.

PM6: “Assumed de novo, but without confirmation of paternity and maternity.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. Variant is a de novo variant: A de novo variant is defined as a variant with zygosity heterozygote (on autosome or on chromosome X for female) or HEMI (on chromosome X for male) for the proband and reference for the parents (parents have to be unaffected).

  2. The relatedness of the samples has not been confirmed.


PP1: “Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The case should contain at least 2 affected members.

  2. The variant segregates with the disease within the pedigree.

  3. The variant is in a gene known to cause a disease with a phenotypic match.

PP2: “Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant must be a missense variant.

  2. The gene has a low rate of benign missense variation and in which, missense variants are a common mechanism of disease. This condition is evaluated by comparing the number of missense pathogenic/likely pathogenic variants reported in ClinVar (with 2-4 stars) to the number of missense benign/likely benign variants reported in ClinVar (with 2-4 stars). The condition is fulfilled if the number of pathogenic/likely pathogenic missense variants is higher or equal to twice the number of benign/likely benign missense variants.

  3. At least 10 missense variants with 2-4 stars were submitted to ClinVar for this gene.

Note: The tag isn't relevant for mtDNA variants and won't be automatically applied to them.

PP3: “Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact).”

For this criterion, we are checking the fulfillment of at least 2 out of the 3 following conditions:

  1. The conservation prediction score is HIGH.

  2. The splicing prediction score is HIGH.

  3. The variant effect is predicted to be damaging.

PP4: “Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.”

This criterion is not currently automated, however, the user can manually enter the corresponding information on the UI.

PP5: “Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant was reported in ClinVar as Pathogenic or Likely Pathogenic with 2-4 stars.

  2. Supporting evidence from functional studies is not available. For this, we are checking the publications associated with ClinVar submissions and if any of them contain functional studies.

Note: The tag isn't relevant for mtDNA variants and won't be automatically applied to them.


BA1: “Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, ExAC or Gnomad (not comprising Gnomad other) and Local database if >1000.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant has an allele frequency > 5% in the relevant population statistic database.


BS1: “Allele frequency is greater than expected for the disorder.”

This criterion is not currently automated, however the user can manually enter the corresponding information on the UI.

BS2: “Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.”

This criterion is partially automated, however the user can manually enter the corresponding information on the UI.

  1. The variant has been observed in a population statistics database.

  2. The observed zygosity for the variant is similar to the one described in the population statistics database.

  3. The associated disease should occur at an early age (age of onset < 10 years old).

  4. The disease should have 100% penetrance.

BS3: “Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant was reported in ClinVar as Benign or Likely Benign with 2-4 stars.

  2. Supporting evidence from functional studies is available. For this, we are checking the publications associated with ClinVar submission and if any of them contains functional studies.

On the UI interface the user also has the possibility to add a publication supporting no damaging effect on the gene or gene product.

BS4: “Lack of segregation in affected members of a family.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The case is not a singleton.

  2. The variant is not segregating with the disease within the pedigree.


BP1: “Missense variant in a gene for which primarily truncating variants are known to cause disease.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant must be a missense.

  2. Primarily truncating variants are known to cause disease for this gene. This condition is evaluated by comparing the number of missense pathogenic/likely pathogenic variants reported in ClinVar (with 2-4 stars) to the number of missense benign/likely benign variants reported in ClinVar (with 2-4 stars). The condition is fulfilled if the number of benign/likely benign missense variants is higher or equal to 5 times the number of pathogenic/likely pathogenic missense variants.

  3. At least 10 missense variants with 2-4 stars were submitted to ClinVar for this gene.

Note: The tag isn't relevant for mtDNA variants and won't be automatically applied to them.

BP2: “Observed in trans with a pathogenic variant for a fully penetrant dominant gene / disorder or observed in cis with a pathogenic variant in any inheritance pattern.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The case must contain the parents.

  2. The variant must be compound heterozygote.

  3. The second variant (in trans) must be reported as pathogenic/likely pathogenic in ClinVar (with 2-4 stars).

  4. The disease inheritance mode must be dominant.

Or the fulfillment to the following conditions:

  1. The case must contain the parents.

  2. There is a variant in cis which has been reported pathogenic or likely pathogenic in ClinVar (with 2-4 stars).

BP3: “In-frame deletions/insertions in a repetitive region without a known function.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant is an in-frame insertion or deletion variant.

  2. The variant is within a repeat region. The repeat regions used are the ones as defined by Repeat masker data from UCSC.

Note: TheThe tag isn't relevant for mtDNA variants and won't be automatically applied to them.

BP4: “Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The conservation prediction score is not HIGH.

  2. The splicing prediction score is LOW or Unknown.

  3. The variant effect is predicted to be neutral.

BP5: “Variant found in a case with an alternate molecular basis for disease.”

This criterion is not currently automated, however the user can manually enter the corresponding information on the UI.

BP6: “Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant was reported in ClinVar as benign/likely benign with 2-4 stars.

  2. Supporting evidence from functional studies is not available. For this, we are checking the publications associated with ClinVar submission and if any of them contain functional studies.

Note: The tag isn't relevant for mtDNA variants and won't be automatically applied to them.

BP7: “A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.”

For this criterion, we are checking the fulfillment of the following conditions:

  1. The variant must be a synonymous variant.

  2. The splicing prediction score is LOW or Unknown.

  3. The conservation prediction score is not HIGH.

ACMG SNV Classification wizard

Where can I review and edit the ACMG Classification of a SNV?

How do I review and edit the ACMG Classification of a SNV?

Each ACMG tag is represented by an interactive button including checkbox (1), name (2) and evidence strength indicator (3).

Pathogenic criteria are represented by red boxes, while benign criteria boxes are colored green. Each ACMG criterion has three possible states:

  • Neutral (1) - represented by an empty checkbox. Criterion requires further investigation.

  • Negative (2) - represented by a cross. Criterion is not applicable.

  • Positive (3) - represented by a tick and dark color. Criterion is applicable.

Each ACMG tag can be manually checked, unchecked, or set to an undefined state by clicking the interactive button's checkbox element.

To examine in detail or modify the underlying evidence for the particular ACMG tag, select it by clicking on the tag name. The button becomes flood-filled (b), as opposed to it's original, non-selected, state (a).

Upon selection, a description of the criterion and its underlying evidence emerges below. Yes and No radio buttons accompany each piece of evidence. The tag can be assigned if Yes has been selected for all the underlying conditions.

You may modify evidence strength in the Strength dropdown (Stand Alone, Very Strong, Strong, Moderate, Supporting), which will impact both the pathogenicity class and score calculations.

On versions 32.0+, you have the capability to add a note alongside a tag.

After you've modified ACMG classification, you can either save manual changes by pressing the Save button or reset via Revert manual changes. Keep in mind that after saving your edits, Revert manual changes will become unavailable.

ACMG classification of mtDNA variants

The ACMG SNV Classification wizard is available for ACMG classification of tagged mtDNA variants. To classify an mtDNA variant, please manually assign the relevant criteria; the resulting ACMG classification will be calculated automatically.

Variant page sidebar (2.29+)

The collapsible Variant page sidebar allows you to access key case information, connect with Alamut and IGV, and view activity log, all within the Variant page. To expand the sidebar, click the arrow icon on the top right, and click again to collapse it.

The Variant page sidebar consists of three tabs:

  1. Case Info tab displays relevant details about the case: sample names, the location of the BAM files connected to the case (if any), affected vs healthy sample status, and proband phenotypes.

  2. Desktop App tab allows users to manage integration with the IGV and Alamut desktop applications.

  3. Activity tab records variant-level user activities such as tagging a variant, adding comments, drafting variant interpretation notes, and editing the evidence graph. This aids collaboration and ensures a traceable record of variant interpretation.

Integration between emedgene and desktop IGV

In order to enable or disable control of IGV from a web browser, please open your desktop IGV application and follow the instructions:

  1. Go to the View menu and select Preferences.

  1. Go to the Advanced tab.

  1. Select or unselect the Enable port option to enable or disable the feature, respectively.

  1. Save the changes.

That's it!

ACMG CNV Classification wizard

Where can I review and edit the ACMG Classification of a CNV?


How do I review and edit the ACMG Classification of a CNV?

The ACMG CNV Classification wizard features:

  1. Automatically calculated ACMG class | ACMG score

  1. ACMG score sliderdepicting ranges of ACMG score values for each ACMG class and where the current classification falls: Benign: ≤-0.99; Likely Benign: -0.98...-0.90; VUS: -0.89...0.89; Likely Pathogenic: 0.90...0.98; Pathogenic: ≥0.99.

  1. Reclassify button that enables Edit mode

  1. Gene Number:

    • Number of protein-coding RefSeq genes overlapped by the CNV; of these:

  2. Genes affected by breakpoints - protein-coding RefSeq genes affected by CNV's breakpoints, and positions of breakpoints relative to the canonical transcript of each affected gene. Keep in mind that sometimes a breakpoint falls into more than one gene because genes may overlap.

  1. Gene table that provides a summary of the affected protein-coding genes:

    • Gene description:

      • Name - HGNC gene symbol,

      • Strand orientation;

    • Overlap info:

      • Gene - percentage of a gene involved in a CNV,

      • CNV - percentage of a CNV that overlaps with a gene;

    • ClinGen dosage sensitivity scores:

      • TS - ClinGen triplosensitivity score,

      • HI - ClinGen haploinsufficiency score;

    • HI predictors:

      • gnomAD pLI score (colored in red if pLI > 0.9),

      • DECIPHER HI index (colored in red if HI < 10);

    • Canonical transcript:

      • RefSeq ID,

      • 5’ UTR - affected or not,

      • CDS:

        • exons involved out of total,

        • NMD flag if the CNV is predicted to undergo nonsense mediated decay.

        • ClinVar flag if there are Clinvar Path SNV in the last exon

*Criteria with variable score:

  • 2F, 2I;

  • 4A, 4B, 4C, 4D, 4E, 4I, 4J, 4K, 4L, 4M, 4N, 4O;

  • 5A, 5B, 5C, 5E, 5G, 5H.

Evidence section

1) A Pathogenicity box

where you and other users in your group can manually assign variant pathogenicity by selecting an option from the dropdown (Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign).

2) Variant Interpretation notes

that include basic variant details added by the AI Shortlist algorithm.

The notes can be manually edited (Edit text link). In editing mode, Paste icon becomes available. You can select actions from the dropdown menu, including:

  1. Import data from Curate:

  2. Choose from related cases - connect summary notes available for the variant if it was classified in one of your organization's previous cases.

  3. Choose from template - generate variant interpretation using the Variant interpretation template.

3) A See evidence button

to review and modify the automatically assigned genomic variant pathogenicity class. Mostly automated.

5) Sanger Confirmation toggle button

to indicate if the variant should or has been submitted for validation through Sanger sequencing.

Note: Keep in mind that the Evidence section is active only for variants that have been automatically or manually tagged. To enable the Evidence section, you need to assign any tag to the variant under consideration.

Enabling visualization for a VCF case

In a VCF case, read alignment view can be enabled in two ways:

a. Creating a case via API with location of alignment files* defined in JSON;

b. Loading local alignment files* to your case in Emedgene.

Click on the button in the top right corner of the section and select relevant BAM and BAI files stored on your PC. After that, you will be able to select the samples to be shown in the viewer by selecting the corresponding sample names on top of the section.

  • BAM and BAI (or CRAM and CRAI)

The Visualization section features an -based tool for the visual review of alignment data for validation and interpretation of variant calls.

Test Subject track showcases read mapping (in a FASTQ case or a VCF case with ).

Curate* track (34.0+)shows short variants that have an entry in the database.

CurateSV* (34.0+) track shows structural variants that have an entry in the database.

On versions 2.29+, the Visualization section offers two viewing modes: and .

In the Advanced mode, you have more control over track visualization, namely, you can specifically select which and you want to review for each sample.

Since version 32.0, the software calculates the variant score based on a recommended by the ACMG.

Emedgene implementation of the ACMG variant classification for SNV follows the “” published in 2015 by Sue Richards et al. Genetics in medicine 17.5 (2015): 405-423. These guidelines define 28 criteria that address types of evidence for the interpretation of sequence variants.

The variant is not part of the .

The ACMG SNV Classification wizard is located in the of the . It facilitates classification of variant pathogenicity through the and enabling manual review and editing of the tags presented as interactive buttons.

Starting from version 32.0, the ACMG SNV Classification wizard includes a pathogenicity bar that visually represents the .

The wizard is available for tagged sequence variants in disease-associated genes. The results of the classification are also highlighted in the of the . Unlike the wizard, automatically assigned criteria and resulting variant class are shown in the for all variants in disease-associated genes, regardless of their status.

Seven criteria have been removed in compliance with : PM1, PM3, PP2, PP5, BP1, BP3, BP6.

While navigating between variants in the emedgene platform, there is an option to change the genomic position in the full-featured desktop application according to the currently selected variant. How cool is that?

The ACMG CNV Classification wizard is located in the of the . Itis available for tagged genomic variants.

The tool automatically scores sections 1, 2, 3, and partially scores sections 4 and 5 of the , including the full PVS1 calculation required for intragenic variants. All the relevant data is summarized in an accessible table.

This tool is highly accurate and can save 75-90% of manual review time for CNVs ().

Number of established ClinGen genes, i.e., genes with sufficient evidence of dosage sensitivity (defined by having of 3) or dosage insensitivity (scores of 40),

Number of predicted haploinsufficient genes (if applicable) - defined as genes with gnomAD probability of loss of function intolerance (pLI) score ≥0.9 and the DECIPHER HI index ≤10.00.

3’ UTR - affected or not.

Evidence sections. The wizard is designed to allow users to easily edit and rescore each section: a. In each section, the criterion selected is color-coded based on its score (hence, pathogenicity of the piece of evidence): * green indicates negative scores (benign evidence), * grey indicates zero (neutral evidence), and * red indicates positive scores (pathogenic evidence).

b. Clicking on a section box reveals the active criterion, its score, and notes box. Here you can: i. add notes; ii. change the criterion's score .

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If the variant is already in your database, the previously selected pathogenicity will be marked with a Curate logo.

Gene - import Interpretation from )

Variant - import Interpretation from

under the Evidence box links to the where you can assess more extensive evidence and generate an evidence graph for the variant under review.

4)

to review and modify the automatically assigned sequence variant . 23 out of 28 ACMG criteria are automated; the other five should be checked manually. On 32.0+. the software additionally calculates the variant based on a points-based system recommended by the ACMG.

is immediately accessible for cases that have been analyzed from FASTQ or BAM files. If the analysis was performed from VCF files, mapping visualization can be enabled using local BAM files.

IGV
Curate
Curate
enabled read alignment view
Simple
Advanced
Curated data
tracks
Additional
tracks
c. With the _Edit tag_ option, users can modify a particular criterion: 1. select a different criterion within a section, 2. add notes, 3. change the criterion's score [where applicable\*](acmg_cnv_classification_wizard.md#h_6cd626ed23).

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d. You may choose to review and adjust evidence section-by-section using the _Reclassify_ option.
User groups
points-based system
Standards and guidelines for the interpretation of sequence variants
BA1 exception list created by ClinGen
Evidence section
Variant page
automation of 23 out of 28 ACMG criteria
pathogenicity score
Clinical Significance section
Variant page
Clinical Significance section
tagging
Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation (2020)
IGV
Evidence section
Variant page
ACMG/Clingen guidelines
ASHG 2020 abstract
ClinGen's Haploinsufficiency and/or Triplosensitivity scores
Curate
Curate Genes
Curate Variants
Evidence page
ACMG SNV Classification wizard
pathogenicity class
score
ACMG CNV Classification wizard
Visualization
where applicable*

PS1(#h_18f3f38fe0)

PVS1
PS2
PS3
PS4
PM1
PM2
PM3
PM4
PM5
PM6
PP1
PP2
PP3
PP4
PP5
BP1
BP2
BP3
BP4
BP5
BP6
BP7
BS1
BS2
BS3
BS4
BA1
See full compatibility table