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Workbench & Pipeline Updates

Release summary table with convenient links to release notes.

Latest Main

Initial Release

Patches

End of Life

October 16th, 2025

Dec 28, 2025

Nov 12, 2025

March 31st, 2027

June 3rd, 2025

November 24, 2025

August 12, 2025

June 25, 2025

December 31st, 2026

V100.39 Patches

Patches

Date

Hotfix (January 27th, 2026)

New in Emedgene V38.0 (June 3rd, 2025)

Introduction

These Release Notes detail the key new features, enhancements, and bug fixes available in Emedgene v38.0.0.

Release highlights:

Improvements to Analyze-Curate flow: Update an existing Curate variant from Analyze, store ACMG tags in Curate and expanded activity log in Curate.
Updates to the automated ACMG classification module for SNVs for PVS1, PS3 and BS3, PS2 and PM6, PP4, PM3, BP7. All tags include improved evidence, including a graphical interface for PVS1, as well as a new phenotypic specificity model and better identification of functional studies.
New and updated annotations: MANE Select/Clinical for transcript selection, CADD missense prediction annotation & filters, VEP updated to VEP-113.
Many new self-serve capabilities including managing organization databases, configuring AI and carrier analysis settings, DRAGEN callers and more. For Illumina clouds, role assignment is now performed in IAM.
CNV/cytogenetic interpretation improvements including fast manually added variants directly from IGV with coordinates, an automated E2E workflow for cyto arrays from ICA and more.
Voice of Customer: Variants now support multiple tags at a time, Curate has a swagger, including support for variant exports and a delete variant route. We’ve also improved export/reporting of CNV ACMG tags.

Emedgene users can select their preferred version out of any of the past 5 releases. Customers on v33.0 and below should select an upgrade path at this time.

The software release includes the following components, which can be selected independently:

Workbench 38
Pipeline 38

Patches

Date

Update Curate interpretation & store ACMG in Curate

We’ve made three highly requested improvements to our Curate-Analyze flow. Users can now update existing Curate variants from Analyze, store ACMG tags in Curate that can be reused in Analyze. To support these new features, we’ve also expanded the activity logs for Curate entry updates, which now have a full record of changes.

Update Curate for an existing variant

From the Variant Page, the Curate button now has multiple options.

Add: If the variant is not already in your Curate database, you will see an “Add” to Curate button.
Update: If the variant is already in your Curate database, and you have the correct 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:
- Pathogenicity

Store ACMG tags in Curate

The ACMG classification automation SNV variants is now available in Curate. The auto-classification logic, manual adjustment of the auto-classification, and notes have the same functionality as in Analyze. Users with the correct role can edit the ACMG tags and pathogenicity. Other users may view but cannot modify ACMG classifications.

By default, when the card first appears in Curate (when a Curate entry is newly created, either singly or via batch upload), all ACMG tags are unchecked and have no pre-calculations. As soon as a user manually sets or changes any tags, the software recalculates the overall pathogenicity and updates. Users can also update ACMG calculations from Analyze. The logic for each tag change follows the most up-to-date approach in Analyze ACMG.

All changes to ACMG tags or the overall ACMG pathogenicity are logged in the Activities panel under the “Curate ACMG” category including tag activation/inactivation, changes to tag strength and to the overall classification.

Limitation: Editing notes will not record an activity.

When annotating a case with Curate data, the stored ACMG classification will automatically be applied to variants that have a stored ACMG tag curation. The classification will take into account tag status (positive/negative), tag question (yes/no), tag strength and tag notes. The ACMG classification will be marked as coming from Curate.

ACMG updates classification module for SNVs

We’re continuing to update our automated ACMG classification module to the latest guidelines. The overall classification was updated in V37, and the tags update schedule is below.

PVS1 updated according to Abou Tayoun 2018 & Walker 2023 with graphical auto-generated evidence

This release includes a significant update to the logic used for assigning the PVS1 tag, which supports more accurate interpretation of predicted loss-of-function (LoF) variants.

The PVS1 evaluation framework has been updated in accordance with recommendations from Abou Tayoun et al. (2018) and further refinements proposed in Walker et al. (2023).

The new PVS1 logic follows the refined decision-making framework proposed by ClinGen’s Sequence Variant Interpretation Working Group. This framework evaluates whether the variant is predicted to result in loss of function (LoF), whether LoF is a known mechanism of disease for the gene, and then walks through transcript, exon, and functional region-level criteria to determine the appropriate evidence strength (Very Strong, Strong, Moderate, Supporting, or Negative).

The logic has been integrated directly into the variant evaluation process to reflect nuanced criteria, such as:

Exon presence in biologically relevant transcripts
Predicted NMD outcome
Functional significance of the altered region

A visual decision path has been introduced to improve transparency. This evidence graph displays the exact reasoning followed in reaching a PVS1 strength assignment, making it easier for users to audit, review, or explain the classification. Users can now trace each logical step visually, from confirming LoF impact to determining whether a region is protein-critical or exon-skipping disrupts function.

Together, these updates ensure more evidence-driven, transparent, and guideline-compliant application of the PVS1 criterion in variant interpretation workflows.

PS3 + BS3 updated according to Walker 2023; Brnich 2020

PS3 and BS3 are ACMG/AMP criteria based on functional evidence. PS3 is applied when well-established functional studies demonstrate a damaging effect of a variant on the gene or its product, supporting pathogenicity. In contrast, BS3 is used when functional studies show no impact, supporting a benign classification.

In this version, we provide an improved classification framework for PS3 and BS3, although we do not implement the full evaluation proposed by Brnich et al. (2020), which includes detailed assessment of functional assay panels (e.g., number of normal and negative controls, OddsPath) and guidance on tag strength. Instead, we retain a simplified approach with improved accuracy in identifying relevant functional studies. Using a new classifier, we can now more accurately detect publications likely to contain functional evidence for the variant under consideration. Additionally, these studies are now provided within the supporting evidence for these tags, which gives better context for users to understand the classification. Final assignment of tag strength remains the responsibility of the user.

PS2 + PM6 updated according to SVI 2021

According to the 2021 SVI recommendations for de novo criteria PS2 & PM6 (Version 1.1, 2021), the strength of these tags should be modified based on the specificity level of the phenotypic match and whether parentage is confirmed or not (points indicated in parentheses), as follows:

Phenotype highly specific for gene (2,1)
Phenotype consistent with gene but not highly specific (1, 0.5),
Phenotype consistent with gene but not highly specific and high genetic heterogeneity (0.5 , 0.25)

In this version, we modified the tag according to the SVI 2021 updates. First, we check the parental confirmation status as displayed on the lab page. If confirmation is available, PM6 is enabled; if not, PS2 is assigned.

Next, the tag’s strength is determined based on the level of phenotypic match, as indicated by the Phenomeld score. If the score meets the threshold for the PP4 tag, the highest strength level is assigned. If the Phenomeld score is high and exceeds a defined threshold (0.8), the second strength level is applied. If the score is above a moderate threshold (0.4), the third strength level is assigned. If there is no phenotypic match, a zero strength level (fourth level) is given.

PP4 updated according to Biesecker 2024

The original definition of PP4 (phenotype specificity criterion) was that the tag should be applied when a subject’s phenotype or family history is highly specific for a disease with a single genetic etiology. A recent paper by Biesecker et al. reevaluated this criterion and proposed a revised definition, expanding its application beyond single-gene conditions, incorporating diagnostic yield considerations, and suggesting integration with co-segregation evidence (PP1) from additional family members.

To align with this updated approach, and recognizing that diagnostic yield data are often unavailable, we developed an algorithm to assist users in evaluating the PP4 tag within the context of each case and to address the challenges of phenotype specificity matching. In this approach, we first identify relevant high-confidence gene-phenotype associations using our phenotypic matching method (Phenomeld). We then assess specificity by determining the number of genes associated with the phenotypes observed in the subject across the entire genome. We also consider indicative of specificity for rare combinations of phenotypes that were found in very few genes.

The strength of the PP4 tag is determined by the number of genes associated with the phenotype: fewer associated genes indicate stronger evidence. In contrast, common phenotypes with high genetic heterogeneity typically do not support application of the PP4 tag.

We assess PP4 strength based on the specificity of the phenotype as follows:

PP4-Strong - phenotype found with up to 20 genes
PP4-Moderate- phenotype associated with up to 100 genes
PP4-Supporting: phenotype associated with 100–200 genes.

It is important to note that PP4 should only be applied when all phenotypically relevant genes have been tested, typically through exome or genome sequencing.

PM3 updated according to SVI

The automated ACMG classification module for SNVs has updated logic for assigning the PM3 criterion, in alignment with the scoring system recommended by the ClinGen Sequence Variant Interpretation (SVI) Working Group for evaluating variants observed in trans in recessive conditions.

The updated logic now applies a quantitative scoring system to determine the strength of PM3 based on the number and type of observed in-trans occurrences in affected individuals. Based on cumulative points system, PM3 is now assigned at appropriate evidence strengths. PM3 supporting evidence provides insight to the cumulative point system.

BP7 update according to Walker et al. 2023

The automated ACMG classification module for SNVs has updated the BP7 logic based on the refined recommendations from Walker et al. (2023). BP7 is now applied more selectively to synonymous and intronic variants only when there is no predicted impact on splicing, as determined using SpliceAI (≤ 0.1). This update ensures more accurate assignment of BP7 by incorporating splicing predictions in accordance with current best practices for non-coding variant interpretation.

Annotation sources update

For this version, we have prioritized three highly requested annotation sources updates. We’ve added MANE Select/Clinical as a primary source for transcript selection. CADD missense prediction scores have been added and are available for annotation & filtering, and we’ve updated VEP updated to VEP-113.

Mane Select/Clinical

Matched Annotation from NCBI and EMBL-EBI (MANE) is a collaborative project that aims to converge on human gene and transcript annotation to define a genome wide set of representative transcripts and corresponding proteins (when applicable) for human genes.

MANE Select: consists of one transcript at each locus across the genome that is representative of biology at that locus.
MANE Plus Clinical: Includes additional transcripts for genes where MANE Select alone is not sufficient to report all "Pathogenic (P)" or "Likely Pathogenic (LP)" clinical variants available in public resources.

MANE V1.4 will be used in the case pipeline for both GRCh38 and GRCh37 for canonical transcript prioritization according to the following logic MANE SELECT transcripts will be used first, if not available, MANE Plus Clinical will be used, with APPRIS as a 3rd priority. Note that using MANE SELECT and only using MANE Plus Clinical as a second option is the recommended implementation by MANE.

In Curate and for Manually Added Variants, MANE will only be available for GRCh38.

CADD missense prediction scores

Combined Annotation Dependent Depletion (CADD) CADD is a tool for scoring the deleteriousness of single nucleotide variants, multi-nucleotide substitutions as well as insertion/deletions variants in the human genome.

CADD V1.7, a pre-calculated score for SNV & All gnomAD release 4.0 InDels for GRCh37 (liftover of gnomAD InDels) & GRCh38 was added as annotation source.

CADD is a phred scaled score expressing the rank in order of magnitude terms rather than the precise rank itself. For example, reference genome single nucleotide variants at the 10th-% of CADD scores are assigned to CADD-10, top 1% to CADD-20, top 0.1% to CADD-30, etc.

CADD was added to In Silico Prediction card on the Variant Page, and is available for both. Filtering and export on a value between 0-99.

VEP-113 update

Variant Effect Predictor was updated to . Content improvements include support for updated REFSEQ, enhanced structural variant support and a UTRAnnotator.

Self-serve

Organization DB management

The Organization Database Management feature gives users better visibility and control over the databases (DBs) used within their organization. These DBs help improve variant interpretation and are commonly used for filtering known variants (historic or noise) or storing curated findings.

Previously, only internal support staff could view or modify these databases. With this update, users can now independently view, add, edit, and manage DBs relevant to their work, directly through the EMG interface.

All users can view a table listing the current databases configured for their organization. Users with the role Managing Organization DB can add/edit new databases to their organization.

AI shortlist and carrier analysis configuration

The AI Shortlist section in the Organization Settings has been enhanced to provide clearer information about the selected AI models and expanded functionality to support Carrier analysis configuration. Previously, the AI Shortlist section allowed configuration only for Rare Disease analysis, offering two modes: Discovery Mode and Focused Mode. These modes are now explicitly labeled under a new "Rare Diseases" sub-section, improving clarity. With this update, a new sub-section for Carrier analysis has been added. Users can now view and configure AI shortlist methods for carrier-based analysis with the following options:

Known Pathogenic – Prioritizes variants reported as pathogenic or likely pathogenic in known variant databases.
High Severity – Prioritizes variants with high predicted severity.
Known Pathogenic Or High Severity – Combines both approaches to broaden prioritization.

While all users can view the currently configured models for both Rare Disease and Carrier analysis, however, to update configuration user will require role ‘Manage auto analysis tier’.

Configurable QC thresholds

Quality parameters section in Org Settings allows users to configure quality thresholds for the organization. Users with 'Manage Quality Parameters' role can edit the following thresholds:

NGS Quality - Set the Gene list threshold for your organization. Case validations will not be applied for cases with gene list below the gene list threshold.
Array Sample Quality - Set the Array quality thresholds for your organization. If a sample’s quality values meet the criteria below, it will be classified as ‘High’; otherwise, it will be classified as ‘Low’.

Roles management has been migrated to IAM

On Illumina environments, access and permissions are now handled exclusively through IAM, replacing the former User Management section in EMG Settings. As a result, access to the User Management tab (Users card) is disabled and automatically redirects users to the IAM application.

Every Emedgene role is now defined as IAM scope. IAM scopes can be grouped into an IAM role (group of scopes) that can be associated with a user. Link to the IAM console where roles can be assigned and changed is available from your Org Settings:

The available roles for Emedgene in IAM are described in the User Guide.

Please note: In legacy environments, user management remains unchanged.

SV annotation thresholds

The Emedgene CNV annotation pipeline integrates multiple structural variant databases, including allele frequency sources (e.g., gnomAD SV) and variant/region pathogenicity resources (e.g., ClinVar, ClinGen). Annotation is performed based on defined overlap thresholds tailored to the clinical significance of each database category:

Pathogenic/Likely Pathogenic, one side, default is 70%, applied to ClinGen Pathogenic/Likely Pathogenic, ClinVar SV Pathogenic/Likely Pathogenic, Curate Pathogenic/Likely Pathogenic, Curated VCF Pathogenic/Likely Pathogenic.
Uncertain, one side, default is 70%, applied to ClinGen VUS, ClinVar SV VUS, Curate VUS, Curated VCF VUS.
Benign/Likely Benign/population, two-sided, default is 70%, 70%. Applied to ClinGen Benign/Likely Benign, ClinVar SV Benign/Likely Benign, Curate Benign/Likely Benign, Curated VCF Benign/Likely Benign, DECIPHER (population db), DGV Gold (population db), gnomAD SV, 1000 genomes, Organization DBs. [OLL1] [AR2]

With this release, users can now manage and customize these SV overlap thresholds directly within the organization settings, offering greater flexibility and control over annotation logic.

Sample pipeline arguments

A new section has been added to the organization settings, allowing users to view the list of sample pipeline arguments configured for their organization. This includes both mapper and caller parameters used during genomic data processing. Providing visibility into these arguments enhances transparency. To request changes to these pipeline arguments, please contact technical support via email.

Variant caller mapping

Emedgene now allows users to configure which variant callers are used in their sample processing pipeline. Each caller is annotated with its sequencing compatibility (WGS, WES), methodology (e.g., CNV read-depth, small variant, SV split-end), and compatibility requirements across sample, DRGN, and case pipeline versions. By default, SNV and CNV callers are always enabled. Additional callers, such as SV, SMN, and STR can now be selectively activated to match evolving analysis needs. Changes made through this interface will apply to newly processed cases after changing selected callers.

Report timezone

Emedgene now supports customizing the report timezone at the organization level. This setting determines the timezone applied to all report timestamps generated within case analyses. By default, report timestamps follow the system timezone, but with this release, users can define their preferred timezone directly through the organization settings, ensuring alignment with local reporting standards and operational needs.

CNV/cytogenetic interpretation improvements

Manually add variants from IGV

Starting from version 38, you can add a variant to a case directly from IGV. This flow is typically used to adjust or combine calls, and is now much more efficient. Simply click the Add Variant button located at the top right of the visualization card. This opens a popup window where you can enter the variant details. By default, the variant type is set to CNV, and the chromosome and coordinates are pre-filled based on the region currently in view. To adjust the span of the suggested coordinates, zoom in or out in IGV accordingly. You can always modify the variant type and genomic coordinates within the popup.

E2E workflow for cyto arrays from ICA

This release introduces automated case creation in EMG following the successful completion of specific cyto array analyses in BSSH/ICA. The new workflow enables standardized, efficient case generation and reduces manual steps.

Upon analysis completion in the managed ICA project, the system will:

Automatically create a new Array case in EMG
Attach all relevant cyto array output files
Extract metadata from the ICA Sample Sheet and apply it to the case

This integration streamlines the handoff between BSSH/ICA and EMG, minimizes manual data entry, and helps reduce the risk of errors — ultimately accelerating downstream review and interpretation.

New columns available in the Analysis Tools page

Starting from V38, the Analysis Tools table now includes additional columns that can be added to the table:

Cytoband (e.g. 1p36.33)
ISCN nomenclature for DEL/DUP (e.g. del(22)(q11.22q11.22))
Bin Count.

The new columns are available in the columns menu and can be ordered as required from Org Settings. New columns are also sortable and available in report and export.

Voice Of Customer

Multiple tags per variant

This release introduces the ability to assign multiple tags to a single variant, enabling more flexible and expressive workflows across the Emedgene platform. This supports highly requested use cases, such as tagging a variant as both “incidental” (for secondary findings reporting) and “most likely” or “candidate” (for primary relevance), without compromising interpretative clarity.

The multiple tagging capability is controlled via a feature flag in the organization settings. Once enabled, it applies to all new and in-progress cases going forward. Disabling the feature will revert tagging behavior to the previous model, preserving only the last tag assigned per variant.

In addition, several usability improvements have been introduced to the tagging experience:

Tag assignment visibility: Users can now view who assigned each tag directly within the tag selection interface, improving team coordination during variant review.

Selective tag removal: When multiple tagging is enabled, users can remove specific tags they've assigned without affecting other users tag assignment.
Supervisor tag management: A new role allows lab directors and managers to remove tags assigned by other users, supporting more efficient supervisory review.
Improved case interpretation view: The tag filter in the case interpretation interface now displays only tags used within the case, along with the number of variants per tag, enhancing clarity during final report preparation.

New Curate swagger and export API

Curate has a new swagger including the much-requested export API available at:

https://<hostname>.emedgene.com/api/kms/apidoc/swagger or https://<hostname>.emg.illumina.com/api/kms/apidoc/swagger

Full documentation is available in the User Manual, Curate Integrations section.

The following API actions are enabled:

Create a new variant
Search for a variant by chromosome position
Update an existing variant
Delete a variant

Limitation: The export is updated every 24 hours, so any changes made in Curate will be reflected in the following day's export.

Add ACMG CNV tags to report/export

Prior to V38, manual changes to ACMG data for CNV variants (e.g., selecting/deselecting tags, adding notes) were visible on the variant page but not reflected in the report output, leading to inconsistencies—especially when those changes affected the ACMG classification and score.

With this update, any manual edits made to ACMG data for CNV variants and resulting change in ACMG score and classification are now fully synchronized across

Report output
Variant interpretation text (via variant interpretation templates)
Case export API

Limitations:

Login | Emedgene does not support accents in User Names, despite support for these in IAM console. Users will not be able to login to the software.
Add New Case | No validation that input files are uncorrupted, case will be created and fail.
Add New Case | Selecting a disease should automatically suggest phenotypes, however, some diseases available for selection are from sources without phenotypes, and in that case, no phenotypes will be suggested.

Fixed Issues:

Analysis Tools | Filters | Removed easily outdated Cancer associated gene list filter. Customers can maintain their own gene lists.
Variant Page | Visualization | Fixed an error showing files not available while they are still loading to desktop IGV.

Known Issues:

Add New Case | For Whole Genome cases, the region of interest BED filter does not filter out CNVs from the CNV and CNV-SV callers.
Add New Case | API | When sending due date please use UTC time, customer time zone is not taken into account with API, only through the UI.
Add New Case | Replacing a sample in the UI will not change the visible sample name.

V38 Patches

Patches

Date

V38.3

November 24, 2025

V38.2

August 12, 2025

V38.1

June 25, 2025

Hotfix (January 21st, 2026)

Pipeline | Fixed multiple issues causing intermittent case failures.
Export/Report | Fixed an issue causing intermittent case export failures.
Propagation from V37 Jan 21st, 2026 hotfix

Hotfix (December 31st, 2025)

Add New Case | Fixed flow for accessioning incidental analysis on parental samples in a trio.
Analysis Tools | Fixed an issue occurring for organizations with variant multi-tag turned on that causes variants tagged by AI to appear as tagged by user.
Analysis Tools | Fixed an issue where CADD score filter was hidden on the UI.

V38.3 Update (November 24th, 2025)

Pipeline | Fixed issues causing case failures.
Cases Page | Fixed an issue where non-admins could move cases in ‘Trash Bin’ status to other statuses.
Curate | Export now includes transcript.

V38.2 Update (August 12th, 2025)

Variant Page | Visualization | Fixed an issue causing Load to Desktop button to fail in V38.
Variant Page | Evidence | ACMG SNV classification | Fixed an issue causing auto-classification to fail when retrieved pubmed author object is empty.
Curate | Export API | Fixed an issue causing variant export to be truncated.

V38.1 Update (June 25th, 2025)

Pipeline | Fixed an issue with new VEP 113 consequences that sometimes affected annotation of CNV duplications.
Variant Page, Analysis Tools | Aligned the source for disease inheritance mode to a unified Emedgene knowledge graph source.
Variant Page | Improved naming of population fields in summary tab to reflect source data.

V36 Patches

Patches

Date

V36.9

November 3, 2025

V36.8

August 11, 2025

V36.7

June 25, 2025

V36.6

May 25, 2025

V36.5

April 6, 2025

Hotfix (January 21st, 2026)

Pipeline | Fixed an issue causing intermittent case failures.

Hotfix (December 31st, 2025)

Fixed annotation errors for GERP and DANN in variants outside of the GERP and DANN source files.

V36.9 Update (November 3rd, 2025)

General security updates

V36.8 Update (August 11th, 2025)

Add New Case | Fixed intermittent issues pushing DRAGEN metrics files (in .tar.gz format) for DRAGEN report generation.
Pipeline | Support for DRAGEN 4.3.17 patch
- For customers running DRAGEN 4.3.17 quality has been adjusted to reflect DRAGEN ML model fix. A variant is designated as Low Quality if the VCF/FILTER is not "PASS" OR the VCF/QUAL is less than 10. Importantly, this change will only affect customers running DRAGEN 4.3.17 and up.

V36.7 Update (June 25th, 2025)

Hotfix deployed on May 28^th: Add New Case | Fixed a reanalysis issue. For some cases, when changing the Regions of Interest BED but not the case type, the new BED was not applied.
Pipeline | DRAGEN 4.3 Star Allele | Fixed an issue causing cases to fail because of unsupported characters in the DRAGEN 4.3 star allele caller.
Organization Settings | Lab Workflow | Presets | Fixed a usability issue that made it difficult to edit multiple presets at once.

V36.6 Update (May 25th, 2025)

Pipeline | DRAGEN 4.3 Targeted | Alignment to DRAGEN quality metrics for the targeted caller output. IF FILTER=PASS then EMG QUAL will be set to HIGH. High quality targeted caller variants are considered by the AI after this fix.
~~Pipeline | DRAGEN 4.3 Star Allele | Fixed an issue causing cases to fail because of unsupported characters in the DRAGEN 4.3 star allele caller.~~ (Fix planned for June 22nd).
Pipeline | Fixed an issue causing cases to remain in status in-progress with no resolution.

V36.5 Update (April 6th, 2025)

Pipeline | Pipeline | Fixed an issue causing cases to be delivered with no AI results after a failure/rerun.
Organization Settings | Preset Filters | Fixed an issue causing presets to erroneously combine when editing multiple preset filters at once.
Propagations from V35.7.

V36.4 Update (March 4th, 2025)

Pipeline | For integrated DRAGEN analyses running on ICA via the ICA runner component, fixed an issue where a ‘.’ In the sample name would fail the analysis.
Pipeline | Fixed an issue where ignore samples in a case was only working for parents.
Analysis Tools | Filters | Fixed an issue causing failures to retrieve variants from the ACMG pathogenicity filter after reanalysis.

V36.3 Update (February 19th, 2025)

Pipeline | Fixed an issue where intermittent and rare pipeline outages caused disruptions in the variant merge logic. No variants are missed, but customers using calling methodology in preset filters in V36.2 might be affected.
Pipeline | Changed DRAGEN 4.3 quality thresholds for SNVs to address an issue in DRAGEN quality. DRAGEN 4.3 ML expanded ML training datasets contained errors in their truth sets, causing the ML model to lower QUAL scores on otherwise clear hom-alt calls.
- A variant is designated as Low Quality if the VCF/FILTER is not "PASS" OR the VCF/QUAL is less than 3.

V36.2 Update (December 11th, 2024)

Organization Settings | DRAGEN arguments | Automatically converting a DRAGEN 4.2 high sensitivity setting ‘vc-enable-high-sensitivity-mode=true’ to the DRAGEN 4.3 equivalent ‘vc-enable-mosaic-detection=true’ to prevent case failure and equivalent outputs.
Add new case | BSSH integration | Fixed an issue causing intermittent errors in VCF ingestion for customers with many BSSH projects.
Add new case | Fixed an issue preventing adding new cases with json files.

V36.1 Update (October 16th, 2024)

Fixed an issue with the DRAGEN targeted.json caller that resulted in missing variants in a case.

V35 Patches

Patches

Date

More release notes

V33 Patches

Patches

Date

V33.3

June 19th, 2024

V33.2

Feb 18th, 2024

V33.1

Jan 14th, 2024

V33.3 hotfix released for the following issues:

Analysis Tools | Preset filters | Fixed an issue introduced with v33.2 that caused some LOF preset filters to not return variants. Customers impacted by this issue were notified individually and resolution offered for potentially affected cases.
Propagation of fixes included in . See release notes for detail.

V33.2 hotfix released for the following issues:

Add New Case | NovaseqX added to selectable sequencers.
Add New Case | Fixed a batch uploader issue where sex column was used correctly but also imported in additional data
Pipeline | Fixed an issue where cases running with DRAGEN 4.2 on HG19 fail the pipeline

V33.1 hotfix released for the following issues:

Add New Case | Fixed issue where new ethnicities added in v32 were not supported for reanalysis in subsequent versions.
Batch Upload | Fixed issue for singleton cases uploaded with batch uploader that resulted in inability to edit cases after creation.
Batch Upload | Fixed issue causing Not Authenticated error for customers with more than 100 BSSH projects.

New pipeline 32 (June 8th 2023)

Updates (February 12th, 2024)

Hotfix released for the following issues:

Pipeline | Fixed a bug that rarely caused discordant AI Shortlist results between a first and second analysis due to model selection.
Pipeline | Fixed an issue causing some reanalysis cases to fail due to insufficient backward compatibility with previous zygosity values. This fix will improve pipeline robustness.

Updates (October 26th, 2023)

Hotfix released for the following issues:

Pipeline | Improved error logging for DRAGEN for easier troubleshooting.
Pipeline | SMN Caller | Fixed multiple issues causing case failures from FASTQ & BAM.
Pipeline | SMN Caller | Fixed issue for GRCh37 & SMN caller where relatedness isn’t calculated due to Peddy failure.

New Features

Improvements to pipeline speed (in hours):

Support for non-GC corrected PONs in the CNV analysis pipeline for panels, in alignment with DRAGEN recommendations.
Updated case status when sample pipeline fails, for quicker troubleshooting and resolution.
Emedgene supports case ingestion from VCF for customer variant callers, as defined in customer’s implementation plans. Several new customer callers were added in this version, and updates made to existing callers. Full documentation is available in the Help Center.

Fixed Issues

Emedgene DRAGEN Pipeline | Save DRAGEN logs for easy troubleshooting of pipeline failures.
Compound Het | Optimized performance to eliminate timeouts during case annotation.

Known Issues

ClinVar sanity check fails case if there are no known variants in ChrY. Workaround: Manual delivery. Fix planned in 33.0.
Visualization is not supported for users storing VCF and CRAM on ICA V1 and BSSH. Only VCF and BAM are supported.

V32 Patches

Patches

Date

New pipeline 5.29 (May 1st 2022)

Updates (August 25th 2022)

Support for DRAGEN 3.10 (support for Graph coming in 5.30)

New in Emedgene 2.28 (May 1 2022)

New Variant Types Supported
1. STR
2. SV Deletion and Duplications

New Variant Types Supported

STR

You can now interpret STRs on Emedgene, including proprietary annotation and visualization.

STRs are available for customers starting from FASTQ. Calling is performed using ExpansionHunter, for which recent specificity/sensitivity data can be found in this publication. Annotation sources include gnomAD and a unique 1K genomes dataset.

This release also includes an easy way to visualize population data as well as the pathogenicity associated with the number of repeats for the variant you are viewing.

SV Deletion and Duplications

Support for SV deletions and duplications for customers starting from FASTQ is now available in all regions. Calling will be performed with the DRAGEN SV caller, and all the interpretation features available for CNVs are applied to SVs, including our time-saving automated ACMG-ClinGen classification.

Gene Curations

Emedgene Curate now supports genes, enabling you to save and view gene interpretations and preferred transcripts.

Private Networking

You can now create private networks and share curated data between organizations in Emedgene Curate. This is in addition to the private networking feature available in emedgene Analyze and enables sharing and transfer of curated data between trusted organizations.

Additional new features

Increased automated ACMG classification accuracy
In the analysis tools table, you can hover on disease to see all related diseases
View allele frequency full decimal number

New in Emedgene 2.26 (Dec 14, 2021)

Emedgene Curate is here!
Increased quality flexibility
Control visualization settings

Emedgene Curate is here!

is a new way to store and manage your organization’s curated data. It forms a single repository for your expert manual curations, across human reference builds and test types. This knowledge management system clearly displays curated data where you need it, in analysis workflows.

When analyzing a case, the , , and sections will clearly highlight that the variant already exists in Emedgene Curate, and provide a link out. You can review curated data and determine whether to reuse it for this case.

If the variant has not been curated, you can export your variant and interpretation.

Easily switch between and Emedgene Curate, using the handy application icon on the left of your browser.

Increased quality flexibility

Version 2.26 adds more flexibility in setting own quality controls. In addition to allele bias and depth, we added the ability to , as well as a new (SNVs).

Control visualization settings

Most Emedgene users utilize two screens when viewing a variant, with one set to their preferred desktop viewer, whether Alamut or IGV. Emedgene automatically changes the desktop viewer as you move between variants.

Now you can whether you’d like the desktop viewer to move between variants automatically or not. If you’re working (from home) on a single screen and not utilizing a desktop browser, you can disable the desktop viewer updates.

API enhancements

The majority of our customers use APIs to add workflow automation and decrease manual labor through connectivity with LIMS, EHR and other health IT systems.

This version improves error tracing when API input doesn’t match expected data, for easier troubleshooting by our respective IT teams.

We’ve also added additional export capabilities using our API.

Improved ethnicity inclusion

We have also expanded the list of ethnicities available during .

New in Emedgene 2.23 (Jun 15, 2021)

New in Emedgene 2.16-2.19 (Dec 7, 2020)

Version 2.19 features improved CNV interpretation capabilities, most notably the ability to add a curated CNV database of chromosomal microarray results. We’ve also enhanced variant visualization, expanded Preset filter capabilities, and added the ability to reflex Case Type up to a broader testing option.

Add your curated CNV database

You can now upload your own curated CNV database, even using historical microarray data. The data can be accessed through a corresponding filter under the Analysis tools > Variant filters in Advanced mode and in the Clinical Significance tab.

Filter by CNV length

We’ve added a CNV Length filter under the to help you filter out small CNVs that are typically noise.

Improved visualization

We’ve added gene names to tracks. You can also conveniently expand/collapse transcripts through a new control panel on the right. Stay tuned for more visualization tracks coming soon.

Reflex case type

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

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

Preset filters by test type

Everyone’s favorite feature, Preset filters, is getting an upgrade. You can now create different Preset filters for each of your test types. We hope this will streamline analysis and save you lots of time.

Enhanced reporting

Are you using our slick new customizable reporting module? We now support all test types AND all variant types. Let us know if you’d like a demo.

Support Help Center

Our live support knowledge base is finally here! If you’re looking for clarifications we’ve loaded answers to our most frequently asked questions, and we will continue to add articles on a weekly basis. You can also conveniently chat with the support team or send us a message.

Support and the new Help Center are accessible at all times via the question mark icon on the platform top bar.

New in Emedgene 2.12-2.16 (Oct 18, 2020)

Automated ACMG/ClinGen CNV classification

The automatically scores sections 1, 2, 3, and partially - sections 4 and 5 of the , including the full PVS1 calculation needed for intragenic variants. It also summarizes all of the pertinent CNV data in an accessible table.

To view the automated classification, simply tag a variant.

According to a small study we ran (), the tool is highly accurate and saves 75-90% of manual review time. Check out a detailed demo on our .

New in Emedgene V38.0 (June 3rd, 2025)

Introduction

These Release Notes detail the key new features, enhancements, and bug fixes available in Emedgene v38.0.0.

Release highlights:

Improvements to Analyze-Curate flow: Update an existing Curate variant from Analyze, store ACMG tags in Curate and expanded activity log in Curate.
Updates to the automated ACMG classification module for SNVs for PVS1, PS3 and BS3, PS2 and PM6, PP4, PM3, BP7. All tags include improved evidence, including a graphical interface for PVS1, as well as a new phenotypic specificity model and better identification of functional studies.
New and updated annotations: MANE Select/Clinical for transcript selection, CADD missense prediction annotation & filters, VEP updated to VEP-113.
Many new self-serve capabilities including managing organization databases, configuring AI and carrier analysis settings, DRAGEN callers and more. For Illumina clouds, role assignment is now performed in IAM.
CNV/cytogenetic interpretation improvements including fast manually added variants directly from IGV with coordinates, an automated E2E workflow for cyto arrays from ICA and more.
Voice of Customer: Variants now support multiple tags at a time, Curate has a swagger, including support for variant exports and a delete variant route. We’ve also improved export/reporting of CNV ACMG tags.

Emedgene users can select their preferred version out of any of the past 5 releases. Customers on v33.0 and below should select an upgrade path at this time.

The software release includes the following components, which can be selected independently:

Workbench 38
Pipeline 38

Patches

Date

Update Curate interpretation & store ACMG in Curate

Update Curate for an existing variant

From the Variant Page, the Curate button now has multiple options.

Add: If the variant is not already in your Curate database, you will see an “Add” to Curate button.
Update: If the variant is already in your Curate database, and you have the correct 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:
- Pathogenicity

Store ACMG tags in Curate

Limitation: Editing notes will not record an activity.

ACMG updates classification module for SNVs

We’re continuing to update our automated ACMG classification module to the latest guidelines. The overall classification was updated in V37, and the tags update schedule is below.

PVS1 updated according to Abou Tayoun 2018 & Walker 2023 with graphical auto-generated evidence

This release includes a significant update to the logic used for assigning the PVS1 tag, which supports more accurate interpretation of predicted loss-of-function (LoF) variants.

The PVS1 evaluation framework has been updated in accordance with recommendations from Abou Tayoun et al. (2018) and further refinements proposed in Walker et al. (2023).

The logic has been integrated directly into the variant evaluation process to reflect nuanced criteria, such as:

Exon presence in biologically relevant transcripts
Predicted NMD outcome
Functional significance of the altered region

Together, these updates ensure more evidence-driven, transparent, and guideline-compliant application of the PVS1 criterion in variant interpretation workflows.

PS3 + BS3 updated according to Walker 2023; Brnich 2020

PS2 + PM6 updated according to SVI 2021

Phenotype highly specific for gene (2,1)
Phenotype consistent with gene but not highly specific (1, 0.5),
Phenotype consistent with gene but not highly specific and high genetic heterogeneity (0.5 , 0.25)

PP4 updated according to Biesecker 2024

We assess PP4 strength based on the specificity of the phenotype as follows:

PP4-Strong - phenotype found with up to 20 genes
PP4-Moderate- phenotype associated with up to 100 genes
PP4-Supporting: phenotype associated with 100–200 genes.

It is important to note that PP4 should only be applied when all phenotypically relevant genes have been tested, typically through exome or genome sequencing.

PM3 updated according to SVI

BP7 update according to Walker et al. 2023

Annotation sources update

Mane Select/Clinical

MANE Select: consists of one transcript at each locus across the genome that is representative of biology at that locus.
MANE Plus Clinical: Includes additional transcripts for genes where MANE Select alone is not sufficient to report all "Pathogenic (P)" or "Likely Pathogenic (LP)" clinical variants available in public resources.

In Curate and for Manually Added Variants, MANE will only be available for GRCh38.

CADD missense prediction scores

CADD V1.7, a pre-calculated score for SNV & All gnomAD release 4.0 InDels for GRCh37 (liftover of gnomAD InDels) & GRCh38 was added as annotation source.

CADD was added to In Silico Prediction card on the Variant Page, and is available for both. Filtering and export on a value between 0-99.

VEP-113 update

Variant Effect Predictor was updated to . Content improvements include support for updated REFSEQ, enhanced structural variant support and a UTRAnnotator.

Self-serve

Organization DB management

All users can view a table listing the current databases configured for their organization. Users with the role Managing Organization DB can add/edit new databases to their organization.

AI shortlist and carrier analysis configuration

Known Pathogenic – Prioritizes variants reported as pathogenic or likely pathogenic in known variant databases.
High Severity – Prioritizes variants with high predicted severity.
Known Pathogenic Or High Severity – Combines both approaches to broaden prioritization.

While all users can view the currently configured models for both Rare Disease and Carrier analysis, however, to update configuration user will require role ‘Manage auto analysis tier’.

Configurable QC thresholds

Quality parameters section in Org Settings allows users to configure quality thresholds for the organization. Users with 'Manage Quality Parameters' role can edit the following thresholds:

NGS Quality - Set the Gene list threshold for your organization. Case validations will not be applied for cases with gene list below the gene list threshold.
Array Sample Quality - Set the Array quality thresholds for your organization. If a sample’s quality values meet the criteria below, it will be classified as ‘High’; otherwise, it will be classified as ‘Low’.

Roles management has been migrated to IAM

The available roles for Emedgene in IAM are described in the User Guide.

Please note: In legacy environments, user management remains unchanged.

SV annotation thresholds

Pathogenic/Likely Pathogenic, one side, default is 70%, applied to ClinGen Pathogenic/Likely Pathogenic, ClinVar SV Pathogenic/Likely Pathogenic, Curate Pathogenic/Likely Pathogenic, Curated VCF Pathogenic/Likely Pathogenic.
Uncertain, one side, default is 70%, applied to ClinGen VUS, ClinVar SV VUS, Curate VUS, Curated VCF VUS.
Benign/Likely Benign/population, two-sided, default is 70%, 70%. Applied to ClinGen Benign/Likely Benign, ClinVar SV Benign/Likely Benign, Curate Benign/Likely Benign, Curated VCF Benign/Likely Benign, DECIPHER (population db), DGV Gold (population db), gnomAD SV, 1000 genomes, Organization DBs. [OLL1] [AR2]

With this release, users can now manage and customize these SV overlap thresholds directly within the organization settings, offering greater flexibility and control over annotation logic.

Sample pipeline arguments

Variant caller mapping

Report timezone

CNV/cytogenetic interpretation improvements

Manually add variants from IGV

E2E workflow for cyto arrays from ICA

Upon analysis completion in the managed ICA project, the system will:

Automatically create a new Array case in EMG
Attach all relevant cyto array output files
Extract metadata from the ICA Sample Sheet and apply it to the case

This integration streamlines the handoff between BSSH/ICA and EMG, minimizes manual data entry, and helps reduce the risk of errors — ultimately accelerating downstream review and interpretation.

New columns available in the Analysis Tools page

Starting from V38, the Analysis Tools table now includes additional columns that can be added to the table:

Cytoband (e.g. 1p36.33)
ISCN nomenclature for DEL/DUP (e.g. del(22)(q11.22q11.22))
Bin Count.

The new columns are available in the columns menu and can be ordered as required from Org Settings. New columns are also sortable and available in report and export.

Voice Of Customer

Multiple tags per variant

In addition, several usability improvements have been introduced to the tagging experience:

Tag assignment visibility: Users can now view who assigned each tag directly within the tag selection interface, improving team coordination during variant review.

Selective tag removal: When multiple tagging is enabled, users can remove specific tags they've assigned without affecting other users tag assignment.
Supervisor tag management: A new role allows lab directors and managers to remove tags assigned by other users, supporting more efficient supervisory review.
Improved case interpretation view: The tag filter in the case interpretation interface now displays only tags used within the case, along with the number of variants per tag, enhancing clarity during final report preparation.

New Curate swagger and export API

Curate has a new swagger including the much-requested export API available at:

https://<hostname>.emedgene.com/api/kms/apidoc/swagger or https://<hostname>.emg.illumina.com/api/kms/apidoc/swagger

Full documentation is available in the User Manual, Curate Integrations section.

The following API actions are enabled:

Create a new variant
Search for a variant by chromosome position
Update an existing variant
Delete a variant

Limitation: The export is updated every 24 hours, so any changes made in Curate will be reflected in the following day's export.

Add ACMG CNV tags to report/export

With this update, any manual edits made to ACMG data for CNV variants and resulting change in ACMG score and classification are now fully synchronized across

Report output
Variant interpretation text (via variant interpretation templates)
Case export API

Limitations:

Login | Emedgene does not support accents in User Names, despite support for these in IAM console. Users will not be able to login to the software.
Add New Case | No validation that input files are uncorrupted, case will be created and fail.
Add New Case | Selecting a disease should automatically suggest phenotypes, however, some diseases available for selection are from sources without phenotypes, and in that case, no phenotypes will be suggested.

Fixed Issues:

Analysis Tools | Filters | Removed easily outdated Cancer associated gene list filter. Customers can maintain their own gene lists.
Variant Page | Visualization | Fixed an error showing files not available while they are still loading to desktop IGV.

Known Issues:

Add New Case | For Whole Genome cases, the region of interest BED filter does not filter out CNVs from the CNV and CNV-SV callers.
Add New Case | API | When sending due date please use UTC time, customer time zone is not taken into account with API, only through the UI.
Add New Case | Replacing a sample in the UI will not change the visible sample name.

New in Emedgene V37.0 (February 20, 2025)

Release highlights for V37.0 pipeline and workbench

New CNV cytogenetic interpretation features! Genome and chromosome view with karyogram, many new significance, population and lab data tracks on the variant visualization, a new and improved version of the embedded IGV, and del/dup ISCN and cytobands annotations for easy reporting.
Emedgene now supports a seamless cytogenetics visualization, interpretation, curation and reporting flow for Illumina arrays, in combination with DRAGEN array’s newly released CNV caller.
Updates to the automated ACMG classification module for SNVs. The overall classification, PP3/BP4, PM2/BS1/BA1 are updated to the latest guidelines with significantly improved evidence. The user interface and traceability of modifications by users has also been improved.
New granular filtering capabilities added on prediction scores, AF, VCF filter and user actions, including the ability to filter on variants that have not been viewed by the current user. This will enable labs to progressively reduce the number of variants appearing in presets and save time per case.
- When applying a custom preset on the fly, the search for genes will restrict the analysis, rather than applying an OR as before.
Self-serve: Customers can empty trash for cases in Move to Trash status, attach PONs to their kits and download their kit BED files independently of support teams.
Annotations and Quality
- For GRCh38, updated to gnomAD SV 4.1
- SpliceAI update and addition of distance data
Voice of Customer
- New protein domain visualization track
- Customize disease name for reporting

Emedgene users can select their preferred version out of any of the past 5 releases. Users on v32.0 and below should select an upgrade path at this time.

Patches

Date

New CNV/cytogenetic interpretation features!

Get an easy view of the full genome and chromosome, which includes a karyogram, and LogR/TNS, BAF and LOH tracks. Make more informed variant interpretation decisions using the many new visualization tracks we’ve added to the updated embedded IGV interface. Streamline reporting with new del/dup ISCN and cytobands annotations.

New Genome View tab

The Genome View Tab is a powerful feature designed to give users a clear, visual overview of the Copy Number Variation (CNV) events and regions of homozygosity/loss of heterozygosity (ROH/LOH) across the genome for customers interpreting WGS, WES or array data. Segments are color coded based on type - blue for DEL; red for DEL, gold for LOH.

The genome view contains an ideogram and 3 tracks: the LogR (array) or TNS (NGS), a BAF and LOH/ROH.

Users can filter the displayed segments by size.

On the ideogram, users can click on chromosomes to switch to a per-chromosome view. Clicking on any variant within the ideogram will bring up the full variant page while hovering on it will show a popup with additional information.

Updated embedded IGV version for improved accuracy when zooming out

Illumina fixed a limitation of IGV web where when zooming out beyond 3Mbp, IGV used to perform a mean calculation, resulting in unclear BAF and BIGWIG tracks. It now displays the data accurately even when zooming out to the full genome.

Many new visualizations tracks are available on the embedded IGV!

This version adds 7 new visualization tracks for easy interpretation of copy number variants in Emedgene. This is in addition to all existing tracks. To improve usability, each track setting is optimized with redefined height and reference lines. In addition, the variant range is highlighted across all tracks.

Knowledge base tracks

OMIM Track: An OMIM track will display genes associated with disease/s. Clicking an entity will show disease name and OMIM ID, associated gene and inheritance mode. A link to the relevant OMIM page is also available.
ClinGen Dosage Sensitivity Track: The ClinGen track will display genes/regions with dosage sensitivity scores for Haploinsufficiency and Triplosensitivity of 1 (Little evidence), 2 (Emerging evidence), 3 (Sufficient evidence), or 40 (Dosage sensitivity unlikely), with color coding based on score severity. Clicking an entity will reveal genomic details, ClinGen scores, descriptions, and a link to the ClinGen database.

Population data tracks to provide structural variant frequency data

gnomAD SV: Clicking a variant will display allele count (AC), allele frequency (AF), total alleles genotyped (AN), and population-specific data for AFR, AMR, EAS, EUR, and OTH groups.
DGV: Clicking a variant will display ALT type (DEL or DUP), non-reference allele count, allele frequency, total alleles genotyped, and the variant ID for further reference.
Decipher: Clicking a variant will display ALT type, allele count, frequency, total genotyped alleles, and variant ID, helping in case interpretation.

Lab historic data tracks

The lab proprietary historic data track/s are now included in the variant page visualization, in addition to the existing capability to visualize Curated data tracks. This is the same data each case is annotated with. Clicking a variant will display variant type (SNV or CNV), chromosome position (+ end for CNV), het, hom, hemi, AF, last 10 samples.

General

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.

New annotations – cytobands & DEL/DUP ISCN

This version adds cytoband annotation for every variant in the system, as well as ISCN nomenclature for DEL and DUP.

The information is now available for every Variant Page, under Clinical Significance – Variant info and can be populated to reports.

SV population statistic filters

The new SV population databases – gnomAD SV, DGV, Decipher – have also been added to the population statistics filters and enable filtering on allele frequency, allele count and hom/hemi ratio thresholds.

Limitations

Currently the Genome Overview tab display is limited to the 500 largest variants. This limitation will be improved in an upcoming hotfix.

Fixed Issues

Variant Page | Visualization | IGV component no longer performs a mean calculation when zooming out by default, which previously occurred around 3Mbp.

Support for cytogenetic arrays

V37 introduces a full integration with the workflows.

This will allow users to run end-to-end cyto array workflows starting from BSSH and ICA, and connecting directly to Emedgene for tertiary analysis and reporting.

Add New Case now supports Array Case Type

Customers can now create array cases and bring the different array outputs – VCF, quality files and visualization files.

When creating your case (from UI, batch or API), a new case type for ‘Array’ is available. This automatically sets the Region of Interest BED file option to “No Filters”.

Calling DEL, DUP and LOH segments with DRAGEN Array

Customers can now ingest VCFs coming from DRAGEN Array V1.2 – Cyto caller. The reported segments will show up in the Analysis Tools, new Genome View, and in IGV visualization tab.

Support bedgraph files for visualization

Customers can upload (from batch/API) the sample’s associated bedgraphs for LogR and BAF that will later be used in the visualization modules in the Genome View and IGV.

Use array quality metrics

Each sample is associated with the following quality scores: Quality, Sex estimation, Autosomal Call Rate, Call Rate and LogR dev.

The quality score is defined “High” when sample's Call Rate is equal or greater than 0.99 AND sample's LogR is equal or smaller than 0.2.
Otherwise, it will be defined as “Low”.

The full information is shown in Lab tab for Array cases, under the Sample Quality section.

All new ACMG user interface, and updated automated classification module for SNVs

The ACMG SNV classification automation has been updated to adhere to the latest guidelines for the PP3, BP4, PM2, BS1 and BA1 tags as well as the overall classification calculation. Based on user feedback, we have a new user interface for the component which makes it easier to understand tag status and user modifications at-a-glance. Finally, we’ve added a new functionality to reclassify ACMG tags using the latest case data.

All new ACMG automated classification for SNVs user interface

The user interface of the ACMG SNV classification component has been refreshed for an easier at-a-glance view of the classification. The pathogenic and benign components have been separated, and the visibility of the applied strength per tag has been improved. ACMG tags will now have visible traceability for all user actions. Any manual change to a tag question, strength and status will be highlighted with the user icon. The user can compare the original results vs the user changes and review the live update of the variant ACMG classification and score.

ACMG Reclassify

ACMG classification will now have a new capability to reclassify ACMG using the case data. This new ability should help when reanalyzing old cases using new pipelines, where the user classification will not be overridden automatically by the reanalysis. You can reclassify to check the output of the automated component with the new annotation data, and also cancel to maintain original classification.

PP3 + BP4 update

A recent study by Pejaver et al. (2022) has introduced new frameworks for calibrating in silico prediction tools to ensure consistent application in clinical variant interpretation. This study proposed specific REVEL score thresholds for missense variant prediction for assignment of PP3 and BP4 strengths BP4: Very Strong <0.003, Strong 0.003-0.016, Moderate 0.016-0.183, Supporting 0.183-0.290; PP3: Supporting 0.644-0.773, Moderate 0.773-0.932, Strong >0.932. In addition, Walker et al. (2023) recommended applying a similar threshold-based approach for splicing predictions using SpliceAI, with thresholds set at 0.1 for BP4 and 0.2 for PP3. This allows for the appropriate weighting of computational evidence for splicing-impact predictions in addition to missense prediction.

Following these recommendations, these thresholds have been adopted in this Emedgene version, and the logic for assigning PP3 and BP4 has been updated to ensure more accurate, consistent, and evidence-based variant classification.

PM2 + BS1 update

In this version, the logic for BS1 and PM2 tags has been improved by implementing gene-specific allele frequency thresholds. These thresholds are determined based on known ClinVar variant allele frequencies for the gene and the disease’s mode of inheritance.

For BS1, the tag is now automatically calculated and enabled if the variant's allele frequency exceeds the established gene-level threshold. The BS1 tag will not be applied together with BA1 to avoid conflicts in classification. The gene-specific threshold is calculated using the maximum population frequency of all ClinVar pathogenic or likely pathogenic variants with at least one-star review status in the gene.

For PM2 in genes associated with autosomal dominant (AD) diseases, the frequency threshold is always set at 0.01%. For autosomal recessive (AR) genes, the threshold is set at 1% if ClinVar data is unavailable. When ClinVar data is available, the threshold is determined by the highest allele frequency of the most common P/LP variant with at least one-star status in ClinVar (using continental allele frequencies). If this frequency exceeds 1%, a 1% threshold is applied to prevent assigning PM2 to common variants. When no data is available, the default threshold remains 1%.

This update ensures that the logic for BS1 and PM2 is more accurate and tailored to each gene’s characteristics and clinical significance, improving the consistency and reliability of variant interpretation.

SNV ACMG overall classification automation logic update

In this version, we enhanced the overall variant classification calculation following the full ACMG tagging process. To reduce bias, similar criteria are no longer counted twice, and the weight distribution among ACMG tags was adjusted. Additional rules were incorporated to improve the accuracy and consistency of the final variant classification according to the latest recommendations.

PP3 and PM4 are not counted with PVS1 (Abou Tayoun et al., 2018).
PP5 and BP6 are not considered in the final classification (Biesecker et al 2018) unless manually applied by the user.
PM2 has been downgraded to Supporting strength (PM2_SVI , 2020).

Known Issues

Variant Page | ACMG Automation | Reclassify is only available for cases that were run with pipeline v37.0, reclassify button might be visible for cases not eligble.

Variant Page | ACMG Automation | Evidence text might not be accurate when new no double dipping logic is enabled.

Variant Page | ACMG Automation | When manually changing a tag status from inactive to active and back again, tag status might be incorrect.

New filtering capabilities – user actions & prediction scores

More filtering capabilities have been added based on customer feedback. The user actions filters have been organized and enhanced, with a new viewed/unviewed filter which allows labs to reduce the variants seen in progressive filters. A new missense prediction category has been added as well as enhanced population statistics and the ability to filter on the VCF filter status. Emedgene added a new ability to intersect on the fly search with existing filters or presets.

User action filters

Under the ‘Evidence & tags’ filter section, in simple mode the user can apply basic filters based on the follow user actions: all tags by current user, all tags by AI shortlist, all viewed variants and all un-viewed variants by the current user.

In the advanced mode, the user can apply specific more filters such as view variants assigned a specific pathogenicity, variants tagged by a specific tag by users, or by AI shortlist.

All these new filters are available to be used within presets.

‘Viewed’ filter was highly requested by customers. By applying this filter in progressive preset filters, users can review variants only once, and reduce the overall number of variants to review.

In silico prediction filters

A new & comprehensive set of filters on in-silico prediction scores has been added, as many users utilize these within their SOP. In simple mode these enable filtering on the overall missense prediction, conservation prediction and splice prediction presented in the In Silico Predictions card on the Variant Page.

In advanced mode, users can filter on:

Revel scores between 0-1
PrimateAI3D predictions of Benign or Damaging
Z-missense values of -8 to 8

Population statistics SV databases and enhancements

Under the ‘Polymorphism’ filter section advanced mode, Emedgene added the capability to apply SV population statistics databases (DGV, Decipher, gnomAD SV). These new filters are available to be used within presets as well.

For Allele frequency filters, Emedgene changed the possible resolution of the filter to a 0.0001 increment. Allowing users to apply the exact allele frequency filtration they desire per database.

VCF filter

Under the ‘Quality’ filter section advanced mode, Emedgene added a new filter ability based on the VCF ‘Filter’ field. Possible filtering option includes ‘Pass’ or ‘Other values’. Using this filter enables users to filter based on the direct VCF quality parameters.

Search intersect

When applying presets, users requested a capability to perform a sub-filtration on top of the existing applied filtering. Therefore, Emedgene applied a new filtering strategy where once applying a search filter, will create a real time sub-filtration on the preset results.

For example, when a preset is using a gene list based on multiple genes that returns many variants, a user can apply a search filter over the preset for a single gene that is part of that gene list, and the results will return only variants located on that single gene (results can be saved as a Custom Preset if needed).

Limitations

Analysis Tools | Presets | Preset filters v1 schema is deprecated, please upgrade to V2 prior to moving to this version.

Analysis Tools | Filters | DRAGEN SV caller contains a discrepancy between the VCF filter column and format field.

Known Issues

Analysis Tools | Filters | Filtering on prediction scores will intermittently not work for panel cases. Hotfix planned.

Self-Serve: Empty Trash, Attach PON to kit

Every Emedgene release enhances customer control over their account, and reduces reliance on Illumina tech support for account configuration and maintenance.

Empty Trash

In V35.0 we added a new case status 'move to trash' where users can mark cases that they would like to delete from their organization. In this version, we are adding the ability to empty the Trash folder.

The Cases Page has a new Empty Trash button in the upper right navigation.

When clicking on the button, users will receive a warning including the number of cases in the ‘Move to Trash’ folder.

Upon confirmation, an activity will be recorded for the case deletion and if users are opted-in, they will receive an email confirmation.

Attach PON to kit

To support CNV calling in targeted panel and exome cases, DRAGEN employs a panel of normals (PON) approach, using a set of matched normal samples to establish a baseline for CNV event detection.

A PON file contains absolute paths to 'target counts' files of individual matched normal samples. While PON file generation remains unchanged, with this release, customers and support teams can attach PONs to a kit using combined counts files instead of a manual workflow.

In your organization settings page, you will see a new dedicated PON management.

The PON table includes the Kit Name, Kit ID, GC Corrected Status, Human Reference, DRAGEN Version and the Maximum Interval Size.

The PON table is searchable by kit name and any PON in the table is downloadable in CSV format.

If an organization contains PONs that have not been migrated to the table view, a warning will be displayed.

Adding/deleting a PON

To add a PON users must select values for mandatory fields – kit, human reference and DRAGEN version. The kits displayed will include all of the available unique kits to the organization (common kits must be moved to the organization to add a PON).

Only one combined.counts.txt.gz file can be selected from any of the supported storages: AWS S3, BaseSpace, and ICA Storage.

The component will perform a validation to ensure the target interval size does not exceed 250 bp for DRAGEN versions up to 4.2, and 500 bp for versions 4.3 and up. The validation is only performed on the first 1000 rows of the file. GC correction status is inferred from the file header or value formats.

To delete a PON simply click the trash button and approve the confirmation message. A deletion of a PON will record an activity.

To migrate your PONs to this new table please submit a support request to or your bioinformatics support team.

Limitations:

Cases Page | Move to Trash and Empty Trash are not available for in-progress or issue reported cases.

Settings | Add PON to Kit | File browser BSSH integration does not support searching by file name.

Known Issues:

Settings | Add PON to Kit | File browser will extract the wrong file extension if there is a ‘.’ In the file name. This is a display issue, won’t affect validation.

Annotations & Quality Updates

For GRCh38, updated to the gnomAD SV 4.1

In version 37, we now support the latest release of gnomAD SV v4, which includes structural variant data: deletions (DEL), duplications (DUP), and insertions (INS) from 63,046 genome-sequenced unrelated samples.

Unlike the previous GRCh38 release which was a liftover mapping from GRCh37 (dbVAR_nstd166), this version is natively aligned to the GRCh38 human reference, offering improved annotation accuracy, enhanced genome coverage, fewer errors, and a larger sample size. Additionally, it includes homozygote and hemizygote counts, along with direct links to the gnomAD website for detailed variant information. Since gnomAD SV v4 is only available for GRCh38, Emedgene will continue using gnomAD SV v2.1 for the GRCh37 pipeline to avoid errors and inconsistencies associated with liftover mapping.

SpliceAI version update with indels support and distance data

We provide updated annotations for variants with predicted effects on splicing, as described in Jaganathan et al., Cell, 2019. In this version, we updated SpliceAI pre-calculated files to SpliceAI v1.3 for SNVs and now also for indels. This update covers all possible single-nucleotide substitutions (SNVs), 1-base insertions, and 1–4 base deletions. We also added coverage for all gnomAD indels using an additional pre-calculated file (direct communication). The variant annotations are masked (weak values are converted to 0), and calculated using a 50 bp window and are available for both GRCh37 and GRCh38 reference genomes.

In addition to SpliceAI delta scores, which represent the probability that a variant affects splicing, we provide the distance to the position with the largest change in splicing probability. Negative/positive values indicate positions upstream/downstream of the variant based on genomic coordinates.

For STRs, added allele distribution in the quality tab

We are now including an allele distribution table which includes the ‘In repeat’, ‘Flanking’ and ‘Spanning’ information provided in the repeats VCF.

Limitations

For multi-allelic STR variants, the ref will be marked as N/A in the allele distribution table.

Voice of Customer

20% of each Emedgene release is allocated to customer feature requests. Sharp-eyed users will notice a new link to Feature Requests under the ? and Help Center link. We will launch a customer-facing feature request system with voting over the coming weeks.

New protein domain visualization track

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.

Customize disease name for reporting

Emedgene now supports editing the selected disease associated with a gene on the Variant Page, and also customizing the disease name for reporting purposes.

When selecting a new disease from the associated gene disease connection list, the evidence graph will also be modified for the variant.

If none of the associated diseases are appropriate for reporting/exporting purposes, a user can click on the plus button within the component and create a new custom disease name. This disease name can be populated to the report, but will only be stored in the case. Emedgene Curate does not yet support custom gene-disease connections or custom disease names.

Emedgene Curate now displays number of variants and genes, including when searching.

For variants, the count displays the number of total filtered variants from the native curate organization and the number of filtered variant interpretations from the network.

Storage integration with Google Cloud

Emedgene now supports Google Cloud in our no-data-movement storage integrations, which include ICA, BSSH, Amazon S3, Azure Data Lake, Azure Blob, FTP and SFTP.

Read more about storage in your organization.

Added reporting fonts, including for Japanese and Thai

More font reporting options have been added to our reporting server, for lab customization. Reporting content can also be added in Japanese and Thai.

Updated and enhanced Swagger for Emedgene Analyze

We’ve made it easier than ever to integrate into Emedgene APIs, to streamline and automate case accessioning, export and more.

Updated swagger https://[org_name].emg.illumina.com/api/apidoc/swagger#/
Updated article
Updated article

Enhancement

Added the DRAGEN mapping metrics CSV file to the outputs folder.

Known Issues:

Reanalysis | Custom disease is not saved when a case is reanalyzed.

Limitations

Login | Emedgene does not support accents in User Names, despite support for these in IAM console. Users will not be able to login to the software.
Add New Case | No validation that input files are uncorrupted, case will be created and fail.
Add New Case | Selecting a disease should automatically suggest phenotypes, however, some diseases available for selection are from sources without phenotypes, and in that case, no phenotypes will be suggested.

Fixed Issues

Add New Case | Storage | Fixed issues with BSSH storage integration that 1) allows using human readable paths in batch upload, 2) Integration only passes QCPassed datasets.
Add New Case | Fixed a limitation where ICA storage integration did not show linked files from BSSH managed projects.
Add New Case | Fixed a limitation where targeted.json files were not supported in the batch upload.

Known Issues

Add New Case | API | When sending due date please use UTC time, customer time zone is not taken into account with API, only through the UI.
Add New Case | Replacing a sample in the UI will not change the visible sample name.
Edit Case | Reanalysis | If HPO terms were updated between analyses, the reanalysis will not automatically map previous HPO terms to new ones.

New in Emedgene V35.0 (May 22nd 2024)

AI in the analysis tools, multiple panel workflows, haplotypes

Release highlights for both workbench 35.0 and pipeline 35.0:

New AI capabilities: Sort by AI rank & Phenomeld score enhances use of AI models in analysis workflow.
New gene list workflows: Apply multiple gene lists during and after case creation, with full traceability.
Cases page gets two most frequently requested features to improve workload management: assign case to another user, & quality summary.
CNV interpretation improvements: New visualization for target counts bigwig, sort by size, differentiate between variant callers for the application of noise DBs and more.
New customer self-serve capabilities: Batch upload to Curate from the UI with validation, easy move/add of gene lists to organizations, new help center.
Enhanced flexibility for lab implementations: Lab defined region of interest and QC per test type, more QC metrics with DRAGEN reports, custom BED annotations and filtering, efficient API queries.
Expanding applications supported on Emedgene with a new haplotype variant and DRAGEN JSON ingestion support.

Emedgene users can select their preferred version out of any of the past 5 releases. Customers on v30.0 and below should select an upgrade path at this time.

Updates

Patches

Date

AI | Improved AI outputs for use in the interpretation workflow. AI rank and Phenomeld scores available and sortable in analysis tools.

Analysis Tools | Sort by AI rank

AI rank is now available in a sortable, exportable column in the analysis tools.

Emedgene does not provide the AI score as it can bias the analysis; whereas AI rank provides an unbiased method to utilize AI in the interpretation workflow.

If two variants share an identical score they will have the same rank in the column.
A reanalysis will update the AI rank values.

Note: The AI feature was previously called ‘auto analysis’ and has now been renamed ‘AI shortlist’ in the versions tab and when editing the case.

( i ) Requires workbench & pipeline update. Old cases can be rerun to retrieve the rank.

Analysis Tools | Sort by Phenomeld score

Phenomeld score is now available in a sortable, exportable column in the analysis tools, in addition to the available filter. Range is 0-2.

( i ) Requires workbench & pipeline update.

As a reminder, Phenomeld is a proprietary phenotypic match algorithm that estimates the concordance between patient phenotypes and an associated disease. It is an important component in our XAI model.

Phenomeld achieves an AUC of 0.94, and uses ensemble machine learning, which combines several phenotypic match models in order to improve model performance.

The Phenomeld model was validated with two data sets.

Utilizing an internal dataset of 314 well characterized cases, Phenomeld was compared to the open source phen2gene model, as well as to the previous Emedgene Phenomatch model, outperforming both.

A second validation used a set of 4648 ClinVar cases, and compared Phenomeld with phen2gene, where Phenomeld demonstrated improved results.

Apply multiple gene lists at and after case creation

This version improves support for labs that regularly apply multiple gene lists per case.

Add New Case | Apply multiple gene list or add genes to a gene list at case creation, from the UI

When applying a gene list at case creation, you can now create a new gene list comprised of multiple gene lists, or add genes to an existing gene list. The new ‘merged’ gene list will carry the same behavior as any other gene list on the platform.

Choose create a new gene list during add new case. Then, search for a single or multiple gene lists, or add genes to an existing gene list:

( i ) Requires a workbench update.

Analysis Tools | Dynamic gene list and search application to preset filters, with full traceability.

Customers can now dynamically couple a gene list, multiple gene lists, or any other search with their preset filters, and review the restricted subset of preset filters with full traceability. This enhancement addresses the need for users to track the reviewing of different gene lists in their case.

To increase flexibility of analysis, this feature is enabled using the search bar, which is now located above the preset filters.

Simply search for a gene list, multiple gene lists or any other supported search function.

By clicking on the 3 vertical dots, you can save your search as a custom preset filter. If you do not save a custom preset filter, you can still perform the restricted analysis, however it will not be saved, and you will not be able to populate it to a report.

You can then review the case according to any of your saved custom preset filters.

Custom preset filters are saved per case, have a full activity trail and can be automatically populated to a report.

( i ) Requires a workbench update.

Limitations:

Combining gene lists in Add New Case is not available from the API or batch upload.
When creating a new gene list by combining gene lists or other, the maximum number of allowed genes is 10,000.

Cases Page | Assign case to other user & quality summary for improved workload management.

The cases page is getting two of the most requested updates in this version.

Assign cases to users for improved workload management.

Lab directors can now assign cases to users, streamlining workload management within the lab. Previously only users could subscribe to a case.

( i ) Requires a workbench update.

Cases page now displays the case quality summary.

The case quality summary has been added as a column in the cases page. This quick view of case quality will improve workload allocation within the lab. The column is sortable and can also be filtered on.

Hovering on the quality icon will provide a quick summary of findings, indicating failure for case or sample quality, and also pedigree and gene coverage validation.

( i ) Requires a pipeline & workbench update.

CNV Interpretation Improvements | Added target counts BigWig, sort by CNV size & more.

This version adds multiple features aimed at improving CNV interpretation capabilities, an effort that will continue in subsequent versions.

New visualization track = the target counts BigWig is now supported, in addition to the tangent normalized BigWig. This is a BigWig representation of the target counts bins. This new track is available from the UI, batch or API for customers starting from both FASTQ or VCF. ( i ) This feature requires both a pipeline and a workbench update.
Analysis tools – new column for variant length (kb), can be sorted, exported and populated to the report. ( i ) This feature requires a workbench update.

Analysis tools – New filtering capability by calling methodology. While this new feature applies to any variant caller used by customers, it can be used to create filters for CNVs called by the DRAGEN read-depth caller separately from the DRAGEN SV caller, so that customers can apply separate noise databases to each. The new filter appears under the Quality filters. Possible calling methodologies:
- Small variant caller
- CNV read-depth caller

( i ) Requires a pipeline & workbench update.

Annotation is now enabled for CNVs larger than 20M bp. ( i ) Requires pipeline & workbench update
Visualization | Added the copy number value to CNV variants in the proband VCF track. ( i ) Requires pipeline & workbench update.

Visualization | Improved performance for the embedded IGV enables quickly moving between variants when multiple new visualization tracks are selected. ( i ) Requires a workbench update.

Limitations:

Variant Page | ACMG Classifications | Cannot be calculated for CNVs >20M bp.
Curate | Variant size limitation of 10M bp due to a live annotation speed limitation.

Self-Serve: Batch upload to Curate with validation, easy move/create gene lists, new help center.

We continue to enable customers to control their Emedgene accounts, and to reduce their reliance on Illumina support teams.

Batch upload to Curate from the UI, with validation.

Customers can now batch add variants to Curate via the UI, utilizing a simple CSV template. Emedgene software will perform a validation on the upload to ensure compatibility and quality in customer Curate databases.

Simply switch to batch mode in the Add new pane in Curate to download an example CSV file and follow the link for more instructions. Note the size limitation for each upload is 5,000 variants. Multiple concurrent uploads are allowed.

After upload, a ‘toaster’ element will appear at the bottom left of Curate. While the toaster can be closed and the upload will continue, the report on the variants uploaded and any that might have failed or partially failed validation can only be accessed through the toaster.

( i ) This feature requires a workbench update.

Easy add/move gene lists in Management and Add New Case.

It’s easier than ever to create new gene lists in the Management page or Add New Case flow.

When switching to batch mode, both gene symbols and NCBI IDs are accepted.
When pasting a list of NCBI IDs or gene symbols from a CSV file, whether downloaded from an Emedgene staging organization or other, no further manipulation needed and the list is accepted as is.

( i ) This feature requires a workbench update.

We have a new help center!

We’ve made it easier to find and use our help center by moving it to no matter where you are located around the world. Previous local versions had limitations with internal linking, these are now fully removed. The new help center can be accessed at this URL regardless of workbench or pipeline versions.

Limitations:

For Curate batch upload, the maximum file size accepted is 10 MB or 5,000 variants. Customers can perform several concurrent batch uploads if needed.
Customers can navigate away from Curate while waiting for their file to import, however the activity ‘toaster’ will disappear, and no report will be available. A report can be requested from support teams.

Enhanced flexibility for lab implementations

This version adds multiple features that enhance flexibility to implement lab standard operating procedures.

Define a region of interest and QC BED for any test type, previously only customization for test type ‘Custom Panel’ was enabled.
- The region of interest BED, whether default or custom, determines the billing.
  - If the number of variants annotated is <55K, billing is for a panel.

The Region of Interest and QC BED files can be defined from the Add New Case flow in the UI batch upload, and API.

( i ) Requires a pipeline & workbench update.

Many new QC metrics are now available in the Lab Tab through a DRAGEN report integration. If your DRAGEN report is available, a link will be added below the sample name. This feature is available for customers starting from FASTQ or VCF from API (See supported DRAGEN outputs below for details).

( i ) Requires a pipeline & workbench update.

Efficient API queries are here! When fetching details of variant(s) and case(s) via the API, users can now define which values to return, rather than returning all values associated with the query. Each query will return default values, and in addition the fields requested.

Before: Full payload in response

After: Specific payload based on request

( i ) Requires a workbench update.

Support for custom BED annotations & filtering

Customers can now annotate their cases with a BED file, and filter on the variants based on the BED annotation. This feature requires support assistance for implementation.

( i ) Requires a pipeline & workbench update.

Push genes of insufficient coverage to a report

Customers can push lists of genes with insufficient coverage at various thresholds (<=0x, <=5x, <=10x, <=20x; or % of BasesGt20x <=20%, <=50%, <=80%, <=90%) and details (transcript, exons affected, position etc) to a report.

( i ) Requires a workbench update

New haplotype support for DRAGEN star allele JSON.

This version expands the possible applications that can be interpreted and reported on in Emedgene to include haplotype driven applications.

Ingest and annotate the DRAGEN star allele caller JSON file (*.targeted.json) including targeted caller CYP2D6 and CYP2B6 outputs as haplotype variants.
New haplotype variant page displays haplotype, genes affected and quality parameters from DRAGEN.
Haplotype variants can be interpreted and pushed into a report.

( i ) Requires a pipeline & workbench update.

Limitations:

This feature is only available for customers running DRAGEN in ICA, BSSH or server and starting cases from VCF.

Additional improvements to workflows and pipeline

gnomAD PLI scores were added to export csv. ( i ) Requires a workbench update.
ClinVar SV, ClinGen and MitoMap annotations were added to the monthly update automation infrastructure, and will be updated on a monthly basis going forward.
DRAGEN pedigree pipeline, which improves accuracy of de novo calling for WGS, is now available for customers starting from FASTQ. ( i ) Requires pipeline & workbench update.

Limitations:

Add New Case | Input file path cannot contain spaces or parenthesis.
Add New Case | API | Applying multiple panels has a limit of 10,000 genes in total but no error message.
Add New Case | For customers starting from Joint gVCF, please make sure the proband is first in order to see the correct insufficient region calculation.

Fixed Issues:

General | Users on Illumina clouds will now get a warning when they are logged out due to their IAM settings. The warning will prompt for a refresh, preventing loss of work on the Emedgene software. This issue was fixed in v34.2 patch and is re-documented with this release.

General | When there is a mismatch of the number of variants in the VCF and the number of variants in the case, a prominent red warning banner appears on the software. Prior to V35 this banner was organization-wide, flashing up for all users even with unaffected cases. Starting with this version, the warning will be case specific.
Candidate | Evidence Graph | Updated literature links to LitVar2.
Variant Page | Fixed an issue where in some cases OMIM inheritance modes were incorrectly displaying CGD values.

Known Issues:

gnomAD 4.1 fix will be supported in V34.5/V35.1. All gnomAD 4.0 links from the UI are directed to 4.1 data, as there is no way to link directly to 4.0 data. This creates a data<-->link discrepancy as Emedgene annotation data is still on gnomAD 4.0.
Add New Case | Flow to run case as a singleton and add family members in a rerun is temporarily not working for cases starting from FASTQ. Targeted fix for V34.4 & V35.1.
Add New Case | API | When sending due date please use UTC time, customer time zone is not taken into account with API, only through the UI.

New in Emedgene V100.39.0 (October 16th, 2025)

Introduction

These Release Notes detail the key new features, enhancements, and bug fixes available in Emedgene v100.39.0.

Note on version naming: Emedgene has now brought back major versioning and releases will follow major.minor.patch conventions. This is as part of preparations for an IVDR submission in the EU. There are no changes to our release policy, both major and minor versions are selectable by customers.

Release highlights:

Support for DRAGEN 4.4 from VCF. DRAGEN 4.4 boosts CNV capabilities with an Allele Specific Copy Number CNV caller, provides a 30% improvement to SV calling accuracy, has new in-run PON generation capabilities and new targeted callers for WES.
Updates to the automated ACMG classification module for SNVs for PS1, BS2, PP1/BS4,BP5, and the possibility to exclude PP5/BP6 from the auto-calculation. All tags include improved evidence.
- This module is now annotated with the gene-specific ClinGen VCEP guidelines, and an alert appears on variants that require custom curation.
Major improvements to the Emedgene variant and gene external links including Google Scholar, Pubmed, Litvar for publication searches and GeneCC and Monarch for diseases. Importantly, GeneCC includes gene-disease validity strength.
Improved support for MNVs. Emedgene now supports MNV ingestion, annotation and filtering, and each variant is displayed as an MNV and is also split and annotated individually.
Our data sharing capabilities now allow cross-cloud networking, for labs with collaborators outside their cloud region. This is an opt-in, lab-controlled capability, where sharing permissions can be defined granularly per network.
CNV/cytogenetic interpretation improvements including a combination analysis tools and IGV visualization component, support for DRAGEN Array 1.3 including mosaicism and expanded chromosome quality metrics.
Additional voice-of-customer improvements:
- Improvements to the transcript prioritization logic to support customers running panels.
- Genome pipeline speed has been reduced by an additional 30%, so that a typical genome will run in 2:15 hrs.

Emedgene customers can select their preferred version out of any of the past 5 releases. Customers on v34.0 and below should select an upgrade path at this time. V34 end-of-life is October 31^st.

The software release includes the following components, which can be selected independently:

Workbench 100.39
Pipeline 100.39

Patches

Date

Support for DRAGEN 4.4 from VCF

New Features:

This version supports for customers starting from VCF. DRAGEN 4.4 improvements include:

Small Variants: Personalized pangenome and ML model result in a 17.76% reduction in FP+FN.
New! Allele Specific Copy Number (ASCN) caller improves accuracy of CNV calling and outputs LOH segments which are ingested as reportable events in Emedgene.
New! Cytogenetics Modality when enabled on the ASCN CNV caller on WGS achieves CMA-equivalent results.

New in Emedgene:

Support for the Ploidy caller, from DRAGEN 4.4, 4.3 and 4.2 (when starting from VCF).
Support for HLA genes from the Star Allele caller.
Many new quality metrics exposed in the Emedgene user interface.

General compatibility with DRAGEN 4.4 outputs

The following table summarizes the supported DRAGEN 4.4 callers:

Type

DRAGEN Output

FASTQ

VCF (BYOD)

Notes

Supported new CNV callers in DRAGEN 4.4

DRAGEN 4.4 has added many new CNV calling improvements.

The CNV Allele Specific Copy Number (ASCN) caller is available for WGS only, and leverages depth of coverage and B-allele frequencies (BAF) to detect germline copy number aberrations and regions with absence of heterozygosity (AOH). Full is available including limitations.

All of the caller outputs, deletions, duplications and LOH, are supported in Emedgene.

The caller outputs a Minor Allele Copy Number estimation which is displayed in the Emedgene Variant Page | Quality tab, in the Copy Number field, and aims to provide more transparent and informative quality metrics for each variant.

The new display will show a format like [X/Y], where:

X represents the Minor Copy Number (MCN) retrieved from the VCF.
Y is calculated by subtracting MCN from the total Copy Number (CN) (for example, if CN = 4 and MCN = 1, the display will show [1/3]).
If no MCN is available for a particular variant, this additional information will simply not be shown.

This caller also provides Mosaic Alterations Detection, and those variants will display the Mosaic tag in Emedgene, which is also available for filtering.

This caller follows the which are now fully supported in Emedgene.

Customers can also run the CNV ASCN command line as part of the CNV-SV caller, and this is supported in Emedgene.

Limitation: Emedgene does not support the CNV ASCN caller when customer downgrade to the VCF v4.2 spec.

The CNV ASCN caller is also available in a Cytogenetics Modality. The allows the user to visualize CNAs at different resolutions, aiming at providing a more flexible workspace for different use cases.

The new Cytogenetics Modality caller has been evaluated as a replacement for CMA as a first-tier test. with Broad and Quest available, key findings:

High Concordance with CMA: WGS achieved 97.28% concordance with CMA for clinically relevant CNVs and LOH.
WGS provided better breakpoint resolution.
WGS covered over 97% of clinically relevant regions for CNV detection, compared to less than 3% with CMA.

All of the CNV ASCN caller features are available for the Cytogenetics Modality caller as well.

Limitation: All events with the SEGID tag (whole chromosome arm) will be designated as low quality in Emedgene.

In-run PON workflow and PON correlation metrics

DRAGEN v4.4 adds workflow-level support for automatically constructing a PoN (Panel of Normals) from a batch of samples on ICA/BSSH. This new workflow provides batch specific artefact correction and reduces putative false positives by as much as 65% compared to WGS CNV while maintaining recall. It also eliminates need for pre-curated/pre-built normal panel.

Emedgene supports ingestion of VCFs generated from these workflows.

Panel-of-Normals Correlation in DRAGEN Reports

DRAGEN reports (accessible via a hyperlink in the Emedgene lab tab) now include a Panel-of-Normals (PON) Correlation section under the QC tab. This new table displays correlation values between the analyzed sample and a set of normal reference samples, helping assess how closely the sample resembles typical, non-pathogenic profiles.

Each row lists a reference sample ID along with its corresponding correlation score. This information can support quality control and help flag potential outliers or unexpected patterns. The table is also available in the downloadable DRAGEN report for each sample from the cases Lab page in Emedgene.

Example report:

New! Support for DRAGEN Ploidy caller

Starting with Emedgene V100.39.0 Emedgene supports ingestion of the DRAGEN ploidy caller in addition to the ploidy estimation metrics. This support will cover DRAGEN 4.2, 4.3 and 4.4 (from VCF only).

The Variant Page now displays an additional quality metric to help you better assess Copy Number Variant (CNV) results from the Ploidy caller.

A new quality field called "Norm. depth of cov." is now available in the Quality tab of the Variant Page. This metric provides valuable insight into the sequencing coverage depth for CNV variants, helping you make more informed quality assessments. This new quality field appears in the Variant Page | Quality tab | Variant quality card directly after the VCF FILTER information.

Values are automatically calculated and displayed with up to 3 decimal places for precision.

The field only appears when data is available for the specific variant. If no normalized depth of coverage data exists for a variant, the field will not be shown.

New! Support for HLA genes from targeted.json

Starting with Emedgene V100.39.0 and DRAGEN 4.4, Emedgene will support the ingestion of the HLA genes from the targeted.json. Interpretation of this data will follow existing haplotype capabilities for CYP2D6, CYP2B6 and star allele caller outputs.

Limitation: The following HLA genes are not supported – HLA-R, HLA-DRB3, HLA-DRB4, HLA-Y.

DRAGEN 4.4 SV caller updates

Starting with Emedgene V100.39.0 and DRAGEN 4.4, Emedgene will display the Imprecise tag on SV caller outputs.

The IMPRECISE tag indicates that:

The variant's breakpoint locations are approximate rather than exact.
Additional consideration may be needed when interpreting the variant's genomic coordinates.
The variant calling algorithm was unable to determine precise breakpoint boundaries.

In Emedgene, the Imprecise tag will be displayed as a chip in the Variant Page | Clinical Significance tab | Variant Info card, similar to other tags such as Mosaic.

Quality metrics for DRAGEN 4.4

ACMG updates classification module for SNVs

Our most requested feature update by customers has been to annotate this module with gene-specific ClinGen VCEP guidelines, and this has been completed in this release. (If you aren’t yet voting on Emedgene feature requests, they can be accessed from the navigation bar, underneath the help center link. We are prioritizing most-voted feature requests in every release.)

We have also completed the update of our automated ACMG classification module to the latest guidelines according to the table below. All updates to this module have taken into account the upcoming SVCv4 guidelines, and will help accelerate implementation of the new guidelines once those are released.

Specifically in this release we have updated the calculations for PS1, BS2, PP1/BS4, BP5, and added the possibility to exclude PP5/BP6 from the auto-calculation. All tags include improved evidence.

ClinGen VCEP annotation and links to gene-specific classification considerations

We have expanded the ACMG classification experience by integrating gene-specific guidelines from the ClinGen Variant Curation Expert Panels (VCEPs), providing deeper alignment with expert-reviewed standards.

In the ACMG Classification card, variants located within genes that have a released ClinGen specification are now automatically annotated. A dedicated note with an icon is displayed, linking directly to the relevant ClinGen recommendation page at . This enhancement builds on the existing ACMG visual framework by adding a clear, actionable reference to gene-specific classification considerations.

If a variant requires manual review based on these specifications, an alert will notify the user, ensuring that expert guidance is applied where needed.

PS1 updated according to Walker et al. 2023² with improved evidence

PS1 is an ACMG/AMP criterion applied when a variant results in the same functional effect, either amino acid change or splicing impact, as a previously known pathogenic variant, regardless of nucleotide change.

In this version, we refined the logic to support both missense and splice variants. For missense, PS1 is applied when the variant leads to the same amino acid substitution as a ClinVar pathogenic variant on the same codon. For splice variants, PS1 is applied when the variant affects the same splice site or region as a ClinVar pathogenic variant, with similar predicted impact based on SpliceAI and SpliceAI-10K.

Strength is assigned based on variant type, location, and ClinVar classification. Supporting evidence includes links to the ClinVar variant, SpliceAI score, and predicted effect.

To prevent over-weighting, PS1 is excluded from ACMG classification when assigned Supporting strength and matched to a Likely Pathogenic variant. Additionally, When PS1 is used with PVS1 at Very Strong strength, the combined contribution is capped at Very Strong + Supporting (Walker et al. 2023²).

BS2

The BS2 tag supports a benign classification when a variant is observed in healthy individuals for a disorder with full penetrance expected at an early age. This update introduces a structured logic framework to ensure consistent and guideline-compliant application.

The automated ACMG classification module for SNVs has updated logic for assigning the BS2 criterion.

The updated logic now applies a four-part decision framework to determine BS2 activation based on inheritance mode, population frequency, disease onset, and penetrance. These conditions are evaluated using curated inheritance data, public variant databases, and manual review inputs.

BS2 is positively activated when all four conditions are met: the variant’s segregation pattern matches a known inheritance mode (AD, AR, or XLR). The variant is observed in public databases at a frequency inconsistent with full penetrance, and the disease is both early-onset and fully penetrant. Supporting evidence includes the observed inheritance mode and the relevant count from public databases, providing users with clear justification for classification.

PP1/BS4 updated according to Biesecker et al. 20245

PP1 and BS4 are ACMG/AMP criteria based on segregation evidence. PP1 is applied when a variant co-segregates with disease in multiple affected family members, supporting pathogenicity. In contrast, BS4 is used when a variant fails to segregate with disease in affected individuals, supporting a benign classification.

In this version, we provide an updated classification framework for both PP1 and BS4 based on pedigree structure. Inheritance mode, and phenotypic match. For PP1, activation requires the presence of affected relatives, co-segregation of the variant with disease, and a phenotypic match. Strength is calculated based on the number of affected and unaffected family members and mapped to Supporting, Moderate, or Strong.

BS4 is activated when there is at least one additional affected family member and the variant does not segregate with disease, based on genotype mismatch with expected inheritance. BS4 is assigned a Strong evidence level by default.

Supporting evidence for both tags includes the selected gene, disease, inheritance mode, and number of affected/unaffected individuals relevant to the segregation pattern. If coverage data is incomplete, PP1 will display a message indicating that co-segregation cannot be determined.

BP5 updated according to Biesecker et al. 20187

The BP5 tag is used to support a benign classification when a variant is found in a case with an alternate molecular basis for disease. This means that another variant in the same case is more likely to explain the observed phenotype, reducing the likelihood that the variant under evaluation is contributing to the disease.

The automated ACMG classification module for SNVs has updated logic for assigning the BP5 criterion.

BP5 is positively activated when all three conditions are met: the disease is autosomal dominant, a second variant with strong pathogenic evidence and phenotypic match is present, and the AI model indicates that a single variant is likely responsible for the disease. Supporting evidence includes the alternate variant’s identity, gene, and phenotypic score, providing users with transparent context for the classification.

Opt to exclude PP5/BP6 from the overall calculation

PP5 and BP6 are ACMG/AMP criteria based on external assertions. PP5 supports pathogenicity when a reputable source reports a variant as pathogenic, while BP6 supports benign classification when a source reports a variant as benign. However, both tags rely on external claims without independent evidence, which can introduce bias.

In this version, no changes were made to the logic or questions for PP5 or BP6. Instead, we introduced a new configuration option in the Organization Settings that allows users to exclude these tags from ACMG classification. This update aligns with recommendations from Biesecker et al. 2018, which caution against using externally asserted classifications without supporting data.

By default, PP5 and BP6 are excluded from ACMG classification. When excluded, a warning message is displayed in the variant page if either tag is positive. Users with the new ‘manage AI ACMG’ role can toggle this setting and save changes. All updates to this configuration are logged with username and timestamp.

This feature is available starting from case pipeline version 100.39.0 and ensures greater transparency and control over how external assertions are handled in variant interpretation workflows.

References:

Abou Tayoun, A. N., Pesaran, T., DiStefano, M. T., Oza, A., Rehm, H. L., Biesecker, L. G., ... & ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI). (2018). Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Human mutation, 39(11), 1517-1524.‏
Logan C Walker, Miguel de la Hoya, George A R Wiggins et al. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet. 2023 Jul 6;110(7):1046-1067. PMID: 37352859.
Brnich, S. E., Abou Tayoun, A. N., Couch, F. J., Cutting, G. R., Greenblatt, M. S., Heinen, C. D., ... & Berg, J. S. (2019). Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework. Genome medicine, 12(1), 3.‏

New and improved Variant Page external links to Google Scholar, PubMed, GeneCC & more

In response to customer feedback, we’ve significantly improved our Variant Page external links in this version, making it easier to identify relevant literature for interpretation and curation and adding new gene and gene-disease links.

Literature searches are now easier and more comprehensive with Google Scholar, PubMed and LitVar searches for SNV, Indel, mtDNA, CNV and SV variant types, in addition to the existing Genomenon link.

There is a new set of gene links to ClinGen, Decipher, GeneCC and OMIM. GeneCC gene-disease connections have also been added to the Gene-Disease relations, including classification strength. Finally, the Monarch Mondo ID is now displayed for each disease, including the link out and API availability.

New literature search variant links

Located in the Variant page | Clinical Significance tab, under the ‘Resources’ field in the Variant info card. These search links offer several alternatives for variant-specific literature searches to ensure comprehensive coverage of the literature.

The search query construction has taken into account the and current literature on genomic variant information available within publications in order to construct the most comprehensive searches for each variant type and resource.

The query logic is as follows across literature sources:

Small variants: RS ID or HGVS coding change (e.g. c.215C>G) or and protein change (e.g. p.Arg72Gly), applied across affected transcripts and aliases, along with the gene name.
CNVs: ISCN notation or cytoband or location and standard CNV descriptors and gene-level information.
SV insertions: Cytoband or variant details and gene context and standard SV descriptors.

Google Scholar search link

The new Google Scholar search link is available for: SNVs, Indels, mtDNA, CNV deletions and duplications and SV insertion variants.

PubMed search link

The new PubMed search link is available for SNVs, Indels, mtDNA, CNV deletions and duplications and SV insertion variants.

Note: Analysis shows that searching PubMed and PMC (PubMed Central) using protein change (p.) values with single-letter amino acid notation retrieves approximately 44.95% of all relevant literature articles. To improve coverage, variant search links now include an additional query using the single-letter amino acid format in p. notation.

If no structured query is defined for a variant type, the link defaults to the main gene associated with the variant, or in cases of multiple genes, the one used for gene metrics.

LitVar2 search link

A new LitVar2 search link has been added to the ‘Resources’ field under the Variant Info section (Clinical Significance tab) on the variant page, enabling users to search for variant-specific literature.

LitVar2 is an advanced literature searching tool developed by NCBI that connects variants to biomedical publications. Using enhanced text mining, natural language processing, and name normalization, it enables accurate retrieval of variant-specific information and returns consistent results across different variant representations.

LitVar2 search links are available for small variants only (SNVs and Indels).

New gene resources links

A new set of gene resources links is now available on the Variant Page→ Clinical Significance tab, within the newly added ‘Resources’ field under the Gene Metrics card.

These resource links provide direct access to databases that provide detailed information about gene function, associated diseases, inheritance patterns, and clinical relevance. This addition enhances the interpretive context and complements variant-level literature review tools.

Included resources:

OMIM (Online Mendelian Inheritance in Man):
GenCC (Gene Curation Coalition):
ClinGen (Clinical Genome Resource):

Gene-level links are available for the following variant types:

Small variants (SNVs, small indels, including mitochondrial DNA)
STR variants
SV variants

For mtDNA and STR variants, a dedicated gnomAD gene-level link is included.

External links to these resources are presented for the main gene associated with the variant. If the variant affects multiple genes, links are shown for the gene used in the Gene Metrics card.

As part of this update, GeneCards and WikiGenes external links have been removed for all variant types to improve clarity and emphasize high-confidence sources. These resources are no longer supported in the Variant Info card under the Clinical Significance tab.

GenCC gene-disease relationships and classification strength

The Gene Curation Coalition (GenCC) provides standardized gene-disease relationship (GDR) classifications from multiple expert submitters. Unlike many resources that use inconsistent terminology, GenCC enables more reliable GDR assessments by unifying evidence definitions across contributors. Emedgene’s Knowledge Graph now includes the GDR, classification strength, submitter name, submitter's GenCC ID, date of submission/evaluation and inheritance mode as reported by submitter. The GeneCC GDR resource will be updated on a monthly cadence with the rest of the Emedgene Knowledge Graph resources.

The GDR links to GenCC will be displayed in:

Variant Page |Summary Tab | Gene-Related Diseases
Variant Page | Clinical Significance | Gene Metrics | Resources (New)

The GDR information will also be displayed on the Variant Page | Gene’s Related Diseases.

The card will display:

Associated diseases for the variant’s gene
Inheritance mode aggregated from all submitters
Most supportive classification (e.g. Definitive), followed by a count of additional classifications (e.g. Definitive +2)

GenCC is listed last in the source priority order, following OMIM, EMEDGENE, CGD, and Orphanet.

Monarch Initiative MONDO links

The Monarch Initiative is an open-science project that integrates genotype–phenotype data across species using semantic technologies to support disease diagnosis, research, and discovery. The initiative also develops and maintains MONDO, a unified disease ontology that harmonizes disease definitions across multiple sources to enable consistent and computable disease representation.

Monarch MONDO links are displayed in the Variant Page | Summary tab | Gene-Related Diseases.

When evaluating a variant and its associated gene-disease relationships, a Monarch external link is shown for eligible diseases in the Gene-Related Diseases section. This link redirects to the corresponding MONDO entry on the Monarchy Initiative database.

Improved Support for Multi-Nucleotide Variants (MNVs)

Emedgene now supports ingestion, annotation, and filtering of Multi-Nucleotide Variants (MNVs), a class of genetic variants where two or more adjacent nucleotides are substituted simultaneously. This enhancement improves biological accuracy and clinical relevance, especially when nearby substitutions affect the same codon or reading frame.

VCF ingestion, normalization and annotation

MNVs are now properly recognized during VCF ingestion and stored in two forms:

New: As a single combined variant (e.g. AG>TC), representing the full multi-nucleotide change.
Existing: As individual SNVs (e.g. A>T and G>C), for compatibility with existing tools and workflows.

MNVs are now annotated both as combined variants and individual SNVs, Annotations include transcript effect, population frequency, and prediction scores, powered by trusted sources such as VEP, GERP, and ClinVar.

Filtering and preset filters

MNVs are now available in the ‘Variant Type’ filters, are supported across all filterings including Quality. They can also be searched directly using REF/ALT base combinations.

Variant Page for MNVs

MNVs are now shown as a distinct variant type across the Variant Page, using the same layout as SNVs. Key updates include:

Variant Summary and Variant Info: Main effect, transcript, cytoband, zygosity, exon number and dbSNP.
Quality section: VCF filter, base quality, read depth, mapping quality, and genotype quality, with visual indicators (High/ Moderate/ Low).
Connected Variants tab will group MNVs with adjacent SNVs.

Interpretation and reporting

MNVs are fully supported in interpretation workflows, including tagging, pathogenicity assignment and reporting/exporting.

Limitations:

Curate does not support MNVs yet and export to Curate is blocked.
The AI shortlist does not support MNVs.

Note: MNV calling is not turned on by default in DRAGEN. More information can be found in the .

The Emedgene Data Sharing Networks has been supported within cloud region since V32.0. This capability empowers trusted partners to securely share variant information beyond allele frequency, including pathogenicity, phenotypes, ACMG tags . Through a flexible, case-based consent model, collaborating organizations can establish multiple networks with granular control over data sharing levels, configuring the data sharing per network. Labs retain full control over their sharing preferences, supporting both broad collaboration and precise data governance. This architecture not only augments internal lab data but also fosters the democratization of genomic insights across institutions.

Starting in v39, labs can collaborate across cloud environments and geographic regions, expanding the scope of potential collaborations. The same secure, opt-in data sharing module is enabled across any Emedgene cloud.

All existing data sharing network components support cross region sharing.

Analyze | Related Cases
Curate | Related Cases
Curate | Variant search – has a new selector for regions, as the search functionality is not available for all regions concurrently.

Limitation:

If two or more networks share identical workgroup/organization names (possible across cloud regions today), there will be no way to distinguish between them in the UI. Recommendation to ascertain uniqueness of network naming across collaborators.
Network classification no longer appears on the Variant Page | Clinical Significance tab or in the Analysis Tools table.

CNV and Cytogenetic Interpretation Flow Improvements

We're excited to introduce the beta version of our new Analysis Tools tab, which adds the ability to jointly view the analysis tools and a full IGV visualization in a single combined tab. This supports cytogeneticists’ need to view both structured variant data in a tabular format along with visual data in a single pane. New in this release is support for DRAGEN Array v1.3, which adds mosaic calling for Illumina cytogenetic arrays and overall improved CNV calling performance. We’ve also added new DRAGEN Array caller quality metrics.

New combination analysis tools and visualizations (beta)

Users now have a streamlined flow for interpreting variants, with a unified view for both tabular variant details and full IGV visualization capabilities.

On the Analysis Tools tab, there is a New Analysis Tools toggle in the upper right. When turning it on, users will have access to the new tab which will show both the table and the visualization. The visualization is the same IGV available in the Variant Page | Visualization tab with the exact same functionality.

The display window height is draggable to adjust the visualization window for maximum review comfort. To turn off the visualization component, or back on again, a new visualizations icon has been added to the table navigation bar.

Table and visualization interaction

Some Analysis Tools table interactions are changed from the previous analysis tools. A single-click on a variant zooms the visualization to that region, whereas in the previous table it opened a variant page. To open a variant, use a double-click or the newly added ‘Open’ link on the left most side of the table. Once a variant is open, the arrow keys can still be used to navigate between variants.

If no variant is selected, the visualization component will display whole genome view (all chromosomes). Zooming in to a chromosome/variant level will display the more tracks.

Adjustment or merging of calls is performed via the ‘Add Variant’ button in the visualization component, in the same way it is enabled since V38.0 on the embedded IGV. When adjusting the span of the selected variant, the coordinates will be automatically populated to the Add Variant button.

Support for DRAGEN Array V1.3

Emedgene provides an optimized interpretation and visualization solution for cytogenetic samples analyzed DRAGEN Array V1.3. Significant updates in that are now supported in Emedgene:

Mosaic calling and fraction estimation for mosaic events.
Improved accuracy of sex chromosome calling, including pseudo-autosomal regions (PAR).
New QC metrics are available in cytogenetics JSON output.

The following table summarizes the supported DRAGEN 1.3 compatibility:

Type

DRAGEN Array Output

VCF (BYOD)

Notes

Visualizing and interpreting mosaic events

Every mosaic event will have a Mosaic tag, which appears on the Variant Page | Summary and Quality tabs. Users can create Preset Filters on this tag.

Additionally, the Variant Page | Quality Tab will display the Mosaic Fraction metric.

Chromosome-level and sample-level quality metrics

DRAGEN Array V1.3 outputs a that includes more sample-level, chromosome-level, and event-level metrics. When this file is ingested into Emedgene via the automated case creation flow, or a manual one, the quality metrics described below are available.

To view the new metrics, in the Quality Tab, each sample has a link to a DRAGEN report. The DRAGEN report will present:

Sample-Level Metrics

Sample ID
Sample sex
Precent LOH
Copy number median

Chromosome-Level Metrics

Percent heterozygosity
Log R Ratio (LRR) median and deviation
Percent LOH
Copy number median and mean

These metrics are displayed in the DRAGEN Report, accessible from the Sample Quality section of the Lab Page. You can also download the original quality files if provided during case creation.

Additional Voice-of-Customer Improvements

Option to prioritize preferred transcript from Curate

To better support customers interested in leveraging their preferred transcripts from Curate, we have added the possibility to prioritize Curate transcripts as defined in Curate variants. This feature is only enabled for customers who turn on a new organization setting (accessible only via Illumina Bioinformatics support in this version).

The new transcript prioritization logic gives a higher priority to Curated variant transcripts, rank 3, in addition to Curate Gene rank 8.

VEP transcripts are prioritized over EFF transcripts.
If the case is a virtual panel, prioritize transcripts from genes in the case gene list (but not for Boosted Genes type panels).
Prioritize transcripts from Curate variants.

Improved structural variant merging logic

Improved handling for cases with structural variants originating from multiple samples. Starting in this version, structural variants will only be merged when they match based on Chromosome, Position, Reference, Alt and END. Prior to V100.39.0 the END position was not considered.

Genome pipeline speed down to 2:15 hours

We are continuously working to improve our genome pipeline speed for customers running rapid genomes or committed to quick turnaround times. In this release, a typical genome case should roughly 2 hours. This does not include the DRAGEN run time.

Limitation: Customers accessioning via VCF+BAM can expect to experience 4-5 hour run time. We recommend using Joint gVCFs to experience the benefits of DRAGEN pedigree calling or accessioning with gVCFs.

Support for ACMG Secondary Findings v3.3

The ACMG secondary findings v3.3 gene list has been updated in both the XAI and the filters.

For the XAI, when a user selects to receive secondary findings, we will apply the v3.3 gene list, which includes 84 genes.

The All ACMG genes filter has also been updated to reflect this expanded list, including newly added genes: PLN, ABCD1, and CYP27A1.

This update ensures alignment with the latest ACMG recommendations for reporting clinically actionable secondary findings.

Updated default Emedgene Full Genes and Clinical Regions BED files

Emedgene default BED files have been updated with newly released regions from RefSeq_curated (GCF_000001405.40-RS_2024_08) and GenCode v47 to capture additional transcripts introduced in both hg38 and hg19.

This update also presents an opportunity to incorporate the latest ClinVar pathogenic variants and newly recognized RNA genes with disease associations. The new clinical regions (50 bp flanking) and full regions (5 kbp flanking) BED files have been merged with the previous versions to retain coverage of unique older regions. The coding files now focus solely on protein-coding regions (20 bp flanking) from both RefSeq_curated and Gencode and includes selected RNA genes with disease relevance.

Self-Serve Enhancements

Delete a variant in Curate

Users now have the ability to delete entries directly from the Curate interface or via API, eliminating the need to contact support for corrections. From the UI, the delete functionality is accessed via the three dots menu. This functionality is available to users with the appropriate role and includes a confirmation step to ensure data is intentionally removed. Network-only variants, those originating from other organizations, remain protected and cannot be deleted. Once a variant is deleted, it is excluded from analysis pipelines and logged for audit purposes.

Limitation: If the variant was used to annotate an existing case, the link from Analyze to Curate will be broken.

Improved Preset management

The preset management interface has been enhanced to better support users who rely on it frequently. Users can now duplicate existing presets, assign new names, and reuse filters with ease. A new column displays the last update for each preset, and sorting options have been added to organize presets by name, type, or update date. Additionally, preset names are now copyable across all tables, simplifying collaboration and reference.

BYOK integration

Organizations can now configure encryption using their own key management services, commonly referred to as Bring Your Own Key (BYOK), directly within the Organization settings.

BYOK allows institutions to maintain full control over their encryption keys, supporting compliance with data protection regulations such as HIPAA and GDPR. The supported provider is Azure Key Vault. (AWS Key Management Service (KMS) will be added in subsequent versions).

Limitations:

Login | Emedgene does not support accents in User Names, despite support for these in IAM console. Users will not be able to login to the software.
Add New Case | No validation that input files are uncorrupted, case will be created and fail.
Add New Case | Selecting a disease should automatically suggest phenotypes, however, some diseases available for selection are from sources without phenotypes, and in that case, no phenotypes will be suggested.

Fixed Issues:

End-to-End Cyto Array | Fixed an intermittent issue causing case creation failures for E2E cyto workflows.
Pipeline | Transcript Prioritization Logic | RNA gene list has been updated.
- Removed genes with weak evidence: HELLPAR, LINC00237, MEG3, LINC00299, GNAS-AS1

Known Issues:

Add New Case | For Whole Genome cases, the region of interest BED filter does not filter out CNVs from the CNV and CNV-SV callers.
Add New Case | API | When sending due date please use UTC time, customer time zone is not taken into account with API, only through the UI.
Add New Case | Replacing a sample in the UI will not change the visible sample name.

New in Emedgene V32.0 (June 8th 2023)

Patches

Date

V32.3

Feb 12th, 2024

Oct 26th, 2023

New Features (June 8th, 2023)

New AI Shortlist Features and Enhancements

On this version we continued focusing on new AI innovation, with the goal of streamlining workflows and further reducing time-per-case.

AI Shortlist now shortlists mtDNA variants

For users analyzing mtDNA variants in Emedgene, the AI Shortlist will now shortlist SNV/CNV mtDNA variants (homoplasmy or heteroplasmy) that are likely to solve the case.

AI Shortlist now shortlists STR variants

For users analyzing STR variants in Emedgene, the AI Shortlist will now shortlist STR variants with expansion size within the pathogenic range according to gnomAD STR and that are likely to solve the case, with evidence.

AI Shortlist now shortlists SV insertions

For users analyzing SV insertions in Emedgene, the AI Shortlist will now shortlist SV insertions that are likely to solve the case, with evidence. Due to variant calling accuracy limitations, insertions, as well as other CNVs, are considered by the AI Shortlist in addition to the regular SNVs.

Shortlisting with evidence for Carrier Screening

Support for sequential (single parent) carrier status.

This new setting will prioritize variants for carrier status, rather than affected, in order to reduce time per case for expanded carrier screening applications.

AI Shortlist can be configured on the organization level to consider only known P/LP variants or both known and high severity variants.
Analysis type ‘carrier’ should be selected during case accessioning.
Output of the AI Shortlistwill be variants tagged as ‘carrier’ rather than the typical ‘most likely’ and ‘candidates’.

Improved recall for AI Shortlist Focused Mode to 96%

Our AI Shortlist model can be run in two modes, including genes of unknown significance (GUS), labeled Discovery Modeor excluding GUS, labeled Focused Mode. In this version, we improved the recall for the Focused Modeto 96%, nearing the results of our Discovery Mode at 97%. The Focused Mode will display up to 7 SNVs, indels, mtDNA and STR variants, and up to an additional 3 CNV variants.

This new Focused Mode was validated on 3 datasets totaling 330 cases solved by SNV, indel, and CNV variants, and demonstrated 96% recall.

Performance Enhancement

AI Shortlist code was refactored to improve performance, scalability, and clean up errors. A bit-exact validation was performed on 3 datasets totaling 330 cases solved by SNV, indel, and CNV variants. A comparison of the precise ranking of most-likely and candidate variants was performed to ensure recall was not affected for cases solved by SNV, indels or CNV variants.

Full Featured Genome: New! Support for SMN, ROH, Ploidy & BAF visualization

Support for the DRAGEN SMN caller

DRAGEN SMN calls SMN1 and SMN2 copy numbers, enabling the analysis of 95% of SMA cases by determining the absence of the functional SMN1 allele in any copy of SMN. This targeted caller overcomes the challenge in producing complete variant caller results with standard WGS due to a high-similarity duplication of SMN1 and the paralog SMN2. Learn more about the .

SMN1 copy number variants can be shortlisted by the AI Shortlist and interpreted just like other CNVs.
SMN2 copy number can also be reviewed and interpreted as a prognostic biomarker of SMA clinical severity.
Carrier status can be assessed by interpreting SMN1 copy number.

Support for the DRAGEN ROH (Regions of Homozygosity) caller

DRAGEN ROH detects and outputs the runs of homozygosity from whole genome calls on autosomal human chromosomes. Sex chromosomes are ignored. ROH output enables screening and prediction of consanguinity between the parents of the proband subject (see DRAGEN™ Bio-IT Platform documentation for more details about the algorithm).

In Emedgene, the ROH BED will be displayed in the IGV viewer. On hover, ROH score, # of Hom SNPs and # of Het SNPs in the region as well as Location (start to end positions) will be displayed.

Support for the DRAGEN Ploidy estimator

DRAGEN Ploidy estimator is used to assess if there are any copy number variants of complete chromosomes (Trisomy, Monosomy etc). The results of the Ploidy estimator will be displayed on the lab tab. If ploidy estimation is marked as fail, the lab tab will have a warning in the page header. Results will be available to download from the sample quality section. (see DRAGEN™ Bio-IT Platform documentation for more details about the algorithm).

Support for B Allele Frequency visualization

The BAF bigwig file is available to view in the additional tracks, both in simple and advanced modes. It will be available for WES and WGS samples called with the Emedgene DRAGEN pipeline.

To avoid confusion, the TNF track, previously labeled as BigWig, is renamed TNF.

Research genome test type

A new Research Genome test type enables full analysis of a genome with no BED intersect. Most of the newly available variants will receive limited or no annotations. The Research Genome significantly increases time per case and performance and is only recommended for research labs with a need to interpret non-coding variants. The Emedgene Whole Genome test type covers 5Kbp upstream/downstream gene and known variants from the non-coding regions, all of which will be annotated.

Support for Illumina Complete Long Reads Interpretation

Support for the recommended Illumina Complete Long Reads interpretation flow.

Ingests the combined long-read/short-read callers for both SVs and SNVs, along with the long read BAM.
Short read callers supported by Emedgene from VCF can be added as well (CNV read-depth, STR (starting from DRAGEN 4.2)).
Once ingested, ICLR variants will be shortlisted by the AI Shortlist and automated ACMG classification will be applied where relevant.

Limitations

Emedgene does not yet support the interpretation of complex SV variants such as inversions and translocations.
ICLR cases must start from VCF, Emedgene doesn’t support case accessioning from both VCF and FASTQ.

Private sharing of curated data between collaborating organizations in Analyze now include granular sharing permissions per network and opt-in/opt-out per case.
Networks are managed from [Settings | Network]. Here the dedicated network manager can:
- Create networks; Labs can belong to multiple networks.

Currently, to invite other organizations to their network(s), the network manager must reach out to tech support. (Network invitation flow will be enabled in a future version).

Level of sharing of a particular case with a particular network of collaborators is defined by:

Sharing mode set for each data field for a particular network. There are 4 levels of sharing that can be applied to each data field: Mandatory – always shared by default; Not shared – never shared; Restricted – shared in cases with or without patient’s consent to Extended sharing; Extended – shared only in cases with patient’s consent to Extended sharing.

Sharing patterns are defined by the network manager in [Settings | Network]. Data fields that could be shared via Analyze Network include:

Case subject consent for Extended data sharing.

Review details of variants tagged by collaborators within organization network(s) in the [Variant page | Related cases tab].

View modes for [Variant page | Related cases tab]: Simple (check/uncheck Network data from all collaborators) and Advanced (select collaborators).

For each variant, extended sharing details are available at a click, as is the ability to contact a collaborator.

Analysis tools improvements: Exclude variants based on pathogenicity, view Presets & sort columns

Exclude variants based on pathogenicity

Exclude variants from your Preset filters based on their pathogenicity in ClinVar or Curate

Save time by excluding benign variants from your Preset filters. Benign variants can be identified from multiple sources (ClinVar, Curate) and can be excluded, as defined by the user. For ClinVar, the classification can also be matched with a star review classification for more granularity in what you exclude. This filter may be applied to any individual preset bin. Contact to request an update to your Preset filters.

View Presets

Added the ability to view the filters underlying each Preset. For variant analysts working on a preset filter, this will enable a quick refresher on the Preset composition, within the analysis flow.

Actions:

Click on the name of the Preset to review the Preset variants.
Click on the dropdown arrow to expand the Preset definition.
Click on the checkbox to indicate that you have completed your review of this Preset.

Sort columns

Sort any column in the analysis table, with the exception of Phenomatch score (which will be available in v33) and Tags.

Primary and secondary sorting are enabled.

Search alternative allele

In the search bar, we now enable searching by a specific SNV/indel variant following the : >  format.

Spaces are supported.
This search will return an exact match.

Add New Case: Single click batch upload of cases

Case accessioning now enables batch upload of cases from the UI! This single click upload of a case manifest file, allows users without API integrations to easily upload batches of 50 cases at once.

Download the Batch Upload csv template, which is compatible with Sample Sheet v2, adding fields needed for tertiary analysis.
Every field available in manual case creation and API, is included in the template: including Family Id, Case Type, Files Names, Visualization Files, Execute Now, BioSample Name, Relation, Gender, Phenotypes, Phenotypes Id, Boost Genes, Gene List Id, Kit Id, Selected Preset, Due Date, Label Id, Clinical Notes, Opt In, Storage Provider Id, Date Of Birth, Default Project including Additional Fields.
Cases can be created with or without samples, just like in UI and API.

Once the full batch has been uploaded and no issues are identified, the cases will be created and analysis will begin.
Up to 50 cases can be created at once.

Workbench | Workflow Improvements: IGV desktop integration, finalize case & more

Improved IGV desktop integration

The Emedgene variant page contains an IGV web viewer, which has limited functionality compared to IGV desktop. Some users prefer to work in a dual screen set up, with IGV desktop open on a second screen.

Emedgene has an existing IGV desktop API integration for users who start from VCF. In this version, the integration was expanded to users who start from FASTQ or store files in an AWS S3 storage bucket.

By clicking the Load to IGV button, all available BAM/CRAM files will be loaded to the desktop IGV (only if the application is already running), and users can further enhance and customize their viewer.

Case interpretation flow update

Users must select a case interpretation status (confidently solved, likely solved, uncertain, negative) before moving the case status to ‘Finalized’.

Interpretation notes, Gene interpretation and Recommendations are saved even if interpretation status is not selected.

Importantly, finalize case via API remains possible.

Add new case | Create existing gene lists

Increase flexibility to support user workflows by enabling the creation of new gene lists that are identical to existing gene lists from API and UI. This will enable users with a complex and large panel test menu to more accurately manage case creation.

Support for gene lists with up to 10,000 genes

Increase flexibility to support user workflows by enabling the creation of large gene lists. Previous limitation was 900 genes.

Gene lists can be created via API and UI; Very large gene lists (>6700 genes) may return a false error message during creation, despite being successfully created.

New ACMG SNV Scoring!

In order to ease the burden of interpreting Variant of Unknown Significance, we have added a score according to the guidelines in Tavtigian et al., fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat. 2020 Oct;41(10):1734-1737 PMCID: .

* The score appears next to the pathogenicity, along with the ruler familiar to users from CNV ACMG calculations.

Each tag can be edited, and editing will modify the score.

Additional:

API | New query returns a list of genes and NCBI IDs associated to the case phenotypes using the Phenomeld algorithm. This query will help laboratories meet compliance requirements.
Variant Interpretation Paragraph - Now supports Catalan, Spanish, Portuguese, and Hebrew symbols.

New Settings

Manage your own S3 credentials

Users (with the Manager and Manage S3 Credentials) can now manage access to Emedgene AWS S3 buckets for Upload & Outputs, under Settings -> Management.

Users can create up to two access keys.
When creating a new key, there is only one opportunity to save/copy the access key and settings (warning appears).
Users can deactivate keys.

Gene Lists | View NCBI ID associated with a gene symbol; Download gene lists with NCBI IDs

The Emedgene pipeline and platform associates NCBI IDs to gene symbols, and preferentially utilizes NCBI IDs throughout the software to alleviate gene list changes due to gene symbol changes or user errors.

In the Management Page, users can view the NCBI IDs associated to the gene symbols within a list and download gene lists with NCBI IDs for review.

Limitations

The accuracy of the AI Shortlist for the new variants (INS, mtDNA, STR, CNV/SV) depends on the variant calling accuracy. The user should be careful when interpreting these challenging-to-call variants.
The new callers and visualizations – SMN, ROH, Ploidy, BAF - are only available for users running WGS from FASTQ on Emedgene, with the exception of BAF, which is also available for users running WES from FASTQ on Emedgene.
To enable the SMN caller on your account please contact Support.

Fixed Issues

The AI Shortlist typically ignores commonly occurring variants. There is an exception list of common variants known to cause disease. This list was expanded, and now includes:

SV calling from WES | Updated DRAGEN SV command line for exomes, per DRAGEN recommendations.
Disabled STR calling from WES | The DRAGEN ExpansionHunter method is only available for WGS.
Update of the Emedgene UI to use the most updated version of the API, in alignment with the batch uploader and new Add New Case features.

Known Issues

CNV variants larger than 20 Mbp are not annotated with genes name and effect, these variants are shortlisted by default by the AI Shortlist, but ACMG automation is not applied to them. (Fix planned for v33).
GRCh37<-->GRCh38 Liftover not available for older components of Network infrastructure, as a result, [Variant Page | Clinical Significance | Networks Classified] may remain erroneously empty while [Variant page | Related cases tab] shows relevant information. Same gap for manually classified variants.
Zygosity, even when set in extended sharing, may remain blank for older cases. Once you click on a case missing zygosity it will be saved for all future views.

New in Emedgene V34.0 (January 28th 2024)

Release highlights for both workbench 34.0 and pipeline 34.0:

Analysis Tools have gotten an efficiency boost with multiselect variants, variants marked as viewed, and frequently requested new preset filters capabilities.
Powerful new Organization Settings reduce your reliance on Illumina support, including Preset creation, management and validation and new Move to Trash status.
New annotations are available - Illumina’s high performing PrimateAI-3D prediction score and an update to the newly published gnomAD v4.
Lab Tab gets new case quality metrics, Peddy sample contamination, and view single gene coverage metrics.
Workflow improvements – more visualizations for customers starting from VCF, visualize Curate data (SNV and SV), improved login flow and report/export enhancements.

Emedgene users can select their preferred version out of any of the past 5 releases. Users on 29.0 and below should select an upgrade path at this time.

Updates

Patches

Date

Analysis Tools | Increase efficiency with new multiselect variants, viewed/unviewed variants and new preset filters on PrimateAI-3D, REVEL and more

i. Multiselect variants and bulk tag, assign pathogenicity and mark viewed

Increase the efficiency of your analysis by performing bulk actions on variants in the analysis tools. When hovering over any variant a checkbox will appear at the beginning of the row.

Actions available are:

Tag or clear tag from all selected variants.

Assign or clear pathogenicity from all selected variants.

Mark selected variants as viewed/unviewed

These actions are only available for non-finalized cases.

More bulk actions will be included in future versions.

The multiselect feature requires an update to Workbench 34.0.

ii. New feature marks viewed/unviewed variants for increased analysis efficiency

Some variants may appear in multiple preset filters. In order to increase analysis efficiency, variants will appear in bold if they have not been viewed, and will appear in regular font weight if they have been viewed. This clear visual indication on whether a variant was viewed or not will help users avoid reviewed variants more than once.

Viewed/unviewed status is tracked by user. If multiple users are analyzing a case, their viewed/unviewed activity is tracked separately. This activity can be modified via the multiselect tool.

Variant color and weight indicate the following:

The viewed/unviewed feature requires an update to Workbench 34.0.

iii. New preset filter feature: Keep AI Shortlist tagged variants in a preset filter even if tag is changed by user

The majority of Emedgene users begin their workflow by reviewing the AI Shortlist tagged ‘Most Likely’ variants. Prior to 34.0, once a user has changed the tag, for example to ‘In Report’, the variant would no longer appear in the most likely preset filter.

In this version we have added the capability to filter on AI Shortlist tagged variants independently of user tags. These variants will remain in the preset filter even when user modifies their tag. This will facilitate reviews of a case by multiple analysts.

In order to revise your preset filters to this new capability, please contact your regional support team or reach out to .

The keep AI Shortlist tagged variants in filter feature requires an update to Workbench 34.0.

iv. New preset filter capability: Filter on PrimateAI-3D score

Presets can now be set to filter on both PrimateAI-3D scores and PrimateAI-3D predictions. Define a preset to show only variants with a PrimateAI-3D score value greater than a selected threshold and/or define a preset to display variants with a PrimateAI-3D prediction of either D (Damaging) or B (Benign).

This new capability can only be implemented through support teams and is not available from the user interface.

The PrimateAI-3D filter feature requires an update to both Workbench 34.0 and Pipeline 34.0.

v. New preset filter capability: Filter on REVEL score

Presets can now be set to filter on variants with a REVEL score value greater than a selected threshold.

This new capability can only be implemented through support teams and is not available from the user interface.

The REVEL filter feature requires an update to both Workbench 34.0 and Pipeline 34.0.

vi. New preset filter capability: Filter variants using values in the DRAGEN VCF filter field, for example QUAL=PASS

Presets can now be set to filter on DRAGEN VCF filter fields. These presets are exact match, text based. Multiple values can be selected, with an OR applied between them.

This new capability can only be implemented through support teams and is not available from the user interface.

The DRAGEN QUAL filter feature requires an update to both Workbench 34.0 and Pipeline 34.0.

vii. New preset filter capability: Filter variants where severity/main effect is unknown

Presets can now be set to filter on severity/main effect when those fields return an unknown value. This will help create filters for intergenic regions and speed analysis of genomes.

This new capability can only be implemented through support teams and is not available from the user interface.

The DRAGEN QUAL filter feature requires an update to Workbench 34.0.

Limitations

Some new preset filter capabilities can only be configured by Illumina support teams and are not available from the UI yet. Future versions will make them configurable from the UI.
The new Multiselect feature is only available for cases that have not been finalized.
Multiselect is limited to 50 variants at a time.

Organization Settings | Customize, manage & control your organization with these new features

This version introduces new features allowing customers to customize, manage and control their organization without requesting Illumina support. We focused on the most requested features and will progressively enhance the organization tab to cover all configurable organization settings.

i. Create and manage Presets and Preset Groups

Presets are combinations of Filters that serve to implement your interpretation Standard Operating Procedures (SOP) within the Emedgene software. Each Preset filter represents an analysis step, and there is full traceability on which presets have been reviewed by your various team members.

A Preset Group is a combination of Preset filters in a particular order that represents a case analysis workflow. Multiple Preset Groups can be created and used for the analysis of different case types. Preset Groups are designed to adhere to laboratory analysis standards while increasing analysis efficiency.

Up to 34.0, the Preset filters have been implemented to your requirements by Illumina support teams.

Starting in 34.0 you can save your own Presets, Preset Groups and also migrate existing Presets into the new self-managed feature.

As part of this new feature, an automatic and comprehensive schema validation covering over 120 fields and their associated unique values was added for Presets and Preset Groups to ensure validity across organizations.

As always, these new features require specific roles which you can distribute to select team members.

Save Presets:

Saving Preset filters is simple.

Apply any filtration strategy using any of the available filters in either simple or advanced mode.
Click on the three-dot icon and select "Save as preset." Enter a unique name for the Preset (Note: Avoid using non-Latin symbols that don't follow the ISO-5589-1 standard).
Don’t forget to save!

Preset and Preset Group management

A new Lab Workflow tab is now available in the the Organization Settings (click on your initials in the upper right to reach all settings).

In this tab you will be able to:

Manage Presets
Manage Preset Groups
Set a default Preset Group for your organization

a. Manage Presets

This card enables you to perform the following actions on your Presets:

Add New – will redirect you to the analysis tools to create a preset filter as described above.
View Preset contents by pressing on the arrow to the left of the Preset name.
Lock Preset – locked Presets cannot be edited or deleted.

b. Manage Preset Groups

This card contains the Preset Group and Legacy tabs.

Preset Group allows you to perform the following functions on your Preset Groups, which are defined combinations of Presets which will be reviewed in a particular order.

View all existing Preset Groups for your organization.
View the contents of each Preset Group in the table, revealing the list of presets it contains.
Create and edit new Preset Groups:

c. Set a default Preset Group

A default Preset Group for your organization can be set and will be used for all cases without a selected Preset Group.

d. Migrating V1 Legacy Presets to V2 Preset Groups

We highly recommend performing the migration with the assistance of regional support teams.

At the time of your choice, you can elect to migrate your Preset Groups to the new Preset tool. The V1(legacy) tab will display a list of Preset Groups that are only available in the V1 schema and will require a migration activity to the new functionality.

To migrate:

Download the JSON file available for the Preset Group in the legacy tab.
Create a new Preset Group from file and upload the JSON file.

The migration tool will create all Presets contained within the V1 Preset Group, and also order them correctly in the V2 Preset Group.

The V2 Preset Groups have been migrated to a robust schema and the preset import will automatically run a schema validation on over 120 simple and complex fields along with associated values. This robust and automatic schema validation will ensure your Presets and Preset Groups function as expected after the transition.

If any errors are found during the automated validation of any single Preset, the migration will fail and no new Preset Group will be created. A clear error message regarding the Preset that was incorrectly formatted will be provided, at which point you can correct the error and re-upload. We recommend utilizing Illumina regional support teams to correct any such errors.

e. Using both V2 and V1 Preset Groups

If at any point in time you have both V1 and V2 Preset Groups available, you can select either when adding a new case.

When a legacy Preset Group was migrated to the new schema, only the V2 Preset Group will be presented.

f. Migrating Preset Groups from Staging to Production organizations

At any time, you can download a Preset Group from a staging organization, and create a new Preset Group from file in the Production organization.

Note that any Presets utilizing gene list IDs or tags will need to be modified in the production organization.

An error message will appear on gene list IDs, providing the Preset Groups were migrated in the same region. If migrating from one cloud to another, please search and replace all gene list IDs.
Please recreate tags in your Production organization before importing the Preset Group.

The Save/Manage/Migrate Presets and Preset Groups feature requires an update to Workbench 34.0.

ii. New ‘Move to Trash’ status replaces support archive request

Customers can now move cases ready for deletion to the new ‘Move to Trash’ status. This functionality replaces the request to archive cases via Illumina support teams.

Cases in ‘Move to Trash’ status are locked for editing, and only users with the correct roles can move them to another status.

Future versions will enable customers to automate deletion of cases in the ‘Move to Trash’ status according to selectable parameters.

Case Deletion is still a request via , please request that Illumina delete all cases in ‘Move to Trash’ status.

The Move to Trash feature requires an update to both Workbench 34.0.

iii. New organization settings configure default page, analysis table columns

The new organization settings require an update to both Workbench 34.0.

Limitations

Some existing Preset functionality is only available via Illumina support teams – exclude benign, filtering on specific prediction scores and more. Please continue to work with your support team to implement these. Note that the newly introduced schema validation applies to all Preset functionality and any functionality added by support teams will undergo an automated validation.
The additional functionality will be exposed to customers starting in mid-2024 versions.
Complex Preset Groups (or/not conditions between filters) will be added in later 2024 versions. The most commonly requested exclusion of benign variants in Presets is possible today with the assistance of Illumina support teams.

New Annotations: PrimateAI-3D, gnomAD v4

i. Emedgene now includes the newly published Illumina PrimateAI-3D prediction score!

PrimateAI-3D is a deep-learning network trained on 4.5 million common genetic variants from 233 primate species. This state-of-the-art classifier accurately quantifies missense variant pathogenicity in humans, which improves discovery of genes affecting clinical phenotypes.

PrimateAI-3D demonstrated superior performance across 6 datasets in this publication:

PrimateAI-3D has been added to the In Silico prediction scores card on the Variant Page. It provides both a numerical score and also a prediction, which can receive the value D (damaging) or B (benign) per variant. The prediction is based on both the score and the gene, score range for damaging/benign is different per gene.

Emedgene users can also create presets based on either the score or the prediction, and also include either or both in their export.

Learn more about .

The PrimateAI-3D feature requires an update to both Workbench 34.0 and Pipeline 34.0.

II. gnomAD v4 is here!

was published on November 1st, 2023 and we’re excited to make it available in this release so quickly. It contains data from 807,162 total individuals and is nearly 5x larger than the combined v2/v3 releases, and more diverse. Both the exome callset (730,947 individuals) and the genome callset (76,215 individuals) were aligned to build GRCh38 of the human reference genome.

On Emedgene, this dataset replaces both the gnomAD Genome V3 and the gnomAD Exome v2 Liftover data.

gnomAD links have been updated in 32.0 and above.

The gnomAD v4 feature requires an update to both Workbench 34.0 and Pipeline 34.0.

Limitations:

Note that since the gnomAD MID population has less than 1000 samples so it is not taken into account as a valid source.

Lab Tab | New case quality section, Peddy contamination, improved single gene coverage workflow

i. New Case Quality section in the Lab Tab

For all cases with a number of genes above a customer defined threshold, Emedgene performs an additional case quality check. Up to 34.0, results of this quality check were not made available to customers and any failure would cause the case to fail and trigger an Illumina support investigation. Starting with this version, cases will not fail, and the result of the case quality check will be provided to users, so they can determine whether to continue with the analysis.

The Case Quality section contains:

Gene list threshold: reflects the gene list threshold applied for the case quality check (default: 50).
A table displaying the results of the various validations performed:

GnomAD Validation - Ensures that each chromosome contains a minimum of 1 variant annotated with GnomAD. Importantly, this validation applies only to chromosomes with at least 100 SNV variants within defined Kit or coding regions. Possible values are Succeed, Failed, Skipped.
ClinVar Validation - Ensures that each chromosome contains a minimum of 1 variant annotated with ClinVar. Importantly, this validation applies only to chromosomes with at least 100 SNV variants within defined Kit or coding regions. Possible values are Succeed, Failed, Skipped.
Auto Analysis Validation – Ensures that at least one variant was tagged by the Emedgene AI. This validation will not apply in cases with a gene list below the defined threshold. Possible values are Succeed, Failed, Skipped.

When one of the Case Quality checks fails, both the section and the Lab Tab will display an alert.

While the case quality check can identify issues with exome and genome cases, it can often be falsely triggered for small panel cases, and it is recommended to exclude it for these cases by setting an appropriate gene threshold. Panels carved out with BED files can also be excluded, please contact your regional support teams or to set up this exclusion.

The Case Quality feature requires an update to both Workbench 34.0 and Pipeline 34.0.

ii. Lab Tab | New Peddy contamination column

The Lab Tab will now display the results of the Peddy assessment of sample contamination (PMID: ), which calculates a deviation using all the sample alt-alleles, providing a sample specific contamination estimation that can detect human contamination.

A new column titled ‘Contamination’ will display the following values:

Yes - IDR_BAF >=0.300
Likely - 0.241<= IDR_BAF <0.300
Unlikely - 0.200<= IDR_BAF <0.24
No - IDR_BAF <0.200 but not 0

IDR_BAF is the inter-decile range (90th percentile - 10th percentile) of the b-allele frequency. Peddy analyzes a distribution of all sites of alts / (ref + alts) and then reports the difference between the 90th and the 10th percentile. Large values indicated likely sample contamination.

When hovering over the value a tool tip will also display the HET ratio (proportion of sites that were heterozygous) and the HET count (number of heterozygote calls in sampled sites).

The Peddy contamination feature requires an update to both Workbench 34.0 and Pipeline 34.0.

iii. Lab Tab | Workflow improvement – view single gene coverage metrics when analyzing a large panel

Users can now remove all genes in a large gene panel, to quickly search and view for a single gene.

The single gene coverage enhancement requires an update to Workbench 34.0.

General Workflow Improvements: Support BAF, ROH for customers starting from VCF, display Curated data in IGV, improved login and performance for ILMN clouds, new export/report capabilities

i. Support ingestion of additional visualization files for customers starting from VCF via the API and batch upload (but not via the UI). These visualizations were already supported for customers starting from FASTQ (32.0 and up).

BigWig TNS (Tangent Normalized Signal) – The TNS track simplifies and increases reliability of CNV analysis and is available for customers running WGS. File supported: tn.bw.
B-Allele Frequency BigWig – The track aids in CNV and LOH analysis and is available for WES and WGS samples. File supported: baf.bw.
ROH BED file – The Regions of Homozygosity (ROH) plot is a visualization of homozygosity that may suggest the presence of uniparental isodisomy or partial isodisomy and is available for customers running WGS. File supported: roh.bed.

This feature requires an update to Workbench 34.0.

A summary of accepted DRAGEN 4.2 outputs in 34.0:

ii. Visualize Curate data! Visualize both SNV and SV Curated data within the IGV viewer

Curate SNV and Curate SV tracks are available in addition to the ClinVar tracks that were already available
Colors indicate variant pathogenicity:
- Green = Benign/Likely Benign

This feature requires an update to Workbench and Pipeline 34.0.

Logging in to any Emedgene URL on Illumina cloud will first direct you to select your domain, in case a user is active in multiple domains, and then to select a possible workgroup. Workgroups will be displayed if the Emedgene application is assigned, they are part of the domain, and the user logging in belongs to the workgroup.
No need to remember a URL, you can login through app.emg.illumina.com and you will be directed to your domain and workgroup automatically.

If no URL has been assigned to a workgroup, domain admins and workgroup owners can initiate a URL assignment workflow.
Select the following parameters
- The region your domain is in

This feature requires an update to Workbench 34.0.

iv. Add New Case | Batch Upload now supports

Commas within any cell
Whitespace, semicolons & separated values will be ignored and information will be extracted regardless.

This feature requires an update to Workbench 34.0.

v. New frequently requested Export/Reporting fields have been added. Please contact your regional support team or if you’d like to modify your export/report.

Case Level: List of genes with insufficient region based on coverage or BaseGT (for cases that have a gene list applied at case creation)
Case Level: Sequencing lab information, sample quality metrics and pedigree metrics.
Variant Level: SNV and CNV ACMG section.

This feature requires an update to Workbench 34.0.

vi. Analysis Tools | New export to csv capabilities

Exports each missense prediction result as a separate columns: Polyphen2 HDIV, Polyphen2 HVAR, SIFT, MutationTaster, LRT, DANN, REVEL, PrimateAI-3D score, PrimateAI-3D Prediction.
Export of Zygosity for Mother and Father as separate columns, in addition to Proband Zygosity and Other family members Zygosity.
Exports disease inheritance mode (from Disease column).

This feature requires an update to Workbench 34.0, but PrimateAI-3D and REVEL require a pipeline update.

Limitations

CNV variants larger than 20 Mbp are not annotated with genes name and effect, these variants are shortlisted by default by the AI Shortlist, but ACMG automation is not applied to them.
There is still a feature discrepancy for customers running DRAGEN through Emedgene (starting from FASTQ) or outside of Emedgene (starting from VCF).
Export to excel is limited to 32KB in size, which may prevent exports with very large CNVs.

Fixed Issues

Add New Case | Network | Default consent is ‘restricted’.
Add New Case | Batch Upload | Fixed error where customers received a ‘Not Authenticated’ due to a timeout for large uploads.
Add New Case | Fixed an issue for API/batch/UI users trying to create a case from BSSH with 15-20 sample files would timeout.

Known Issues

Add New Case | Batch Upload | Analysis Type field is not available with this version of Batch Upload, and it cannot be used to initiate the new Carrier workflow.
Add New Case | Create a case from case creation summary does not work, please click on top Add New Case button from cases page.
Add New Case | For customers starting from Joint gVCF, please make sure the proband is first in order to see the correct insufficient region calculation.

Version update needed for access to new features

Feature

Workbench 34.0

Pipeline 34.0

References

Pedersen and Quinlan, Who’s Who? Detecting and Resolving Sample Anomalies in Human DNA Sequencing Studies with Peddy, The American Journal of Human Genetics (2017),

Workbench & Pipeline Updates

V100.39 Patches

hashtagHotfix (January 27th, 2026)

New in Emedgene V38.0 (June 3rd, 2025)

hashtagIntroduction

hashtagUpdate Curate interpretation & store ACMG in Curate

hashtagUpdate Curate for an existing variant

hashtagStore ACMG tags in Curate

hashtagACMG updates classification module for SNVs

hashtagPVS1 updated according to Abou Tayoun 2018 & Walker 2023 with graphical auto-generated evidence

hashtagPS3 + BS3 updated according to Walker 2023; Brnich 2020

hashtagPS2 + PM6 updated according to SVI 2021

hashtagPP4 updated according to Biesecker 2024​

hashtagPM3 updated according to SVI

hashtagBP7 update according to Walker et al. 2023

hashtagAnnotation sources update

hashtagMane Select/Clinical

hashtagCADD missense prediction scores

hashtagVEP-113 update

hashtagSelf-serve

hashtagOrganization DB management

hashtagAI shortlist and carrier analysis configuration

hashtagConfigurable QC thresholds

hashtagRoles management has been migrated to IAM

hashtagSV annotation thresholds

hashtagSample pipeline arguments

hashtagVariant caller mapping

hashtagReport timezone

hashtagCNV/cytogenetic interpretation improvements

hashtagManually add variants from IGV

hashtagE2E workflow for cyto arrays from ICA

hashtagNew columns available in the Analysis Tools page

hashtagVoice Of Customer

hashtagMultiple tags per variant

hashtagNew Curate swagger and export API

hashtagAdd ACMG CNV tags to report/export

hashtagLimitations:

hashtagFixed Issues:

hashtagKnown Issues:

V38 Patches

hashtagHotfix (January 21st, 2026)

hashtagHotfix (December 31st, 2025)

hashtagV38.3 Update (November 24th, 2025)

hashtagV38.2 Update (August 12th, 2025)

hashtagV38.1 Update (June 25th, 2025)

V36 Patches

hashtagHotfix (January 21st, 2026)

hashtagHotfix (December 31st, 2025)

hashtagV36.9 Update (November 3rd, 2025)

hashtagV36.8 Update (August 11th, 2025)

hashtagV36.7 Update (June 25th, 2025)

hashtagV36.6 Update (May 25th, 2025)

hashtagV36.5 Update (April 6th, 2025)

hashtagV36.4 Update (March 4th, 2025)

hashtagV36.3 Update (February 19th, 2025)

hashtagV36.2 Update (December 11th, 2024)

hashtagV36.1 Update (October 16th, 2024)

V35 Patches

More release notes

V33 Patches

hashtagV33.3 hotfix released for the following issues:

hashtagV33.2 hotfix released for the following issues:

hashtagV33.1 hotfix released for the following issues:

New pipeline 32 (June 8th 2023)

hashtagUpdates (February 12th, 2024)

hashtagUpdates (October 26th, 2023)

hashtagNew Features

hashtagFixed Issues

hashtagKnown Issues

V32 Patches

New pipeline 5.29 (May 1st 2022)

hashtagUpdates (August 25th 2022)

New in Emedgene 2.28 (May 1 2022)

hashtagNew Variant Types Supported

hashtagSTR

hashtagSV Deletion and Duplications

hashtagGene Curations

hashtagPrivate Networking

hashtagAdditional new features

New in Emedgene 2.26 (Dec 14, 2021)

Hotfix (January 27th, 2026)

Introduction

Update Curate interpretation & store ACMG in Curate

Update Curate for an existing variant

Store ACMG tags in Curate

ACMG updates classification module for SNVs

PVS1 updated according to Abou Tayoun 2018 & Walker 2023 with graphical auto-generated evidence

PS3 + BS3 updated according to Walker 2023; Brnich 2020

PS2 + PM6 updated according to SVI 2021

PP4 updated according to Biesecker 2024

PM3 updated according to SVI

BP7 update according to Walker et al. 2023

Annotation sources update

Mane Select/Clinical

CADD missense prediction scores

VEP-113 update

Self-serve

Organization DB management

AI shortlist and carrier analysis configuration

Configurable QC thresholds

Roles management has been migrated to IAM

SV annotation thresholds

Sample pipeline arguments

Variant caller mapping

Report timezone

CNV/cytogenetic interpretation improvements

Manually add variants from IGV

E2E workflow for cyto arrays from ICA

New columns available in the Analysis Tools page

Voice Of Customer

Multiple tags per variant

New Curate swagger and export API

Add ACMG CNV tags to report/export

Limitations:

Fixed Issues:

Known Issues:

Hotfix (January 21st, 2026)

Hotfix (December 31st, 2025)

V38.3 Update (November 24th, 2025)

V38.2 Update (August 12th, 2025)

V38.1 Update (June 25th, 2025)

Hotfix (January 21st, 2026)

Hotfix (December 31st, 2025)

V36.9 Update (November 3rd, 2025)

V36.8 Update (August 11th, 2025)

V36.7 Update (June 25th, 2025)

V36.6 Update (May 25th, 2025)

V36.5 Update (April 6th, 2025)

V36.4 Update (March 4th, 2025)

V36.3 Update (February 19th, 2025)

V36.2 Update (December 11th, 2024)

V36.1 Update (October 16th, 2024)

V33.3 hotfix released for the following issues:

V33.2 hotfix released for the following issues:

V33.1 hotfix released for the following issues:

Updates (February 12th, 2024)

Updates (October 26th, 2023)

New Features

Fixed Issues

Known Issues

Updates (August 25th 2022)

New Variant Types Supported

STR

SV Deletion and Duplications

Gene Curations

Private Networking

Additional new features

Emedgene Curate is here!

Increased quality flexibility

Control visualization settings

API enhancements

Improved ethnicity inclusion

Hotfix (January 21st, 2026)

Hotfix (December 31st, 2025)

V38.3 Update (November 24th, 2025)

V38.2 Update (August 12th, 2025)

V38.1 Update (June 25th, 2025)

Hotfix (January 27th, 2026)

Updates (August 25th 2022)

Summary of Pipeline 5.29