V34.7 Update (August 13th, 2024)

• This hotfix enables an update of gnomAD 4.1 non-UK Biobank data for SNV.

Due to the extensive changes required to update from gnomAD 4.0 to gnomAD 4.1 non-UKB data, the new gnomAD data will be turned off by default, as we believe some re-verification may be needed before switching to gnomAD 4.1 non-UKB.

A parameter in organization settings, configurable by Illumina support teams has been added to define the gnomAD version.

• The default configuration is for gnomAD_version 4.0.

• Illumina support teams can update this to gnomAD_version 4.1_non-UKB.

This parameter can be configured independently in staging and production environments for customers on Professional or Enterprise plans.

The population summary tab will clearly note whether gnomAD or gnomAD non-UKB was used.

When updating to the gnomAD 4.1 non-UKB data, links will be directed to the non-UKB data.

Versions tab will display the specific gnomAD version used.

This organization setting will be deprecated in the release of V36.0.0, at which time gnomAD 4.1 non-UKB will be the default gnomAD annotation within the Emedgene software.

• Variant Page | Fixed an issue where in some cases OMIM inheritance modes were incorrectly displaying CGD values.

V34.6 Update (August 6th, 2024)

The following fixes are aimed at improving application performance for customers using older personal computers with lower available RAM.

• General | Software will display a performance warning when less than 2Gb of free RAM is available.

• Visualization | Using a desktop IGV version and disabling the embedded IGV will reduce the memory requirements for the Emedgene application.

  • Disable embedded IGV by toggling embedded IGV off and desktop IGV on in the side car links.

  • Push all tracks to desktop IGV. When loading tracks to desktop IGV, now all available tracks will be automatically pushed, with the exception of the ClinVar SV known variant track.
• Variant Page | Embedded IGV | Improved IGV performance by reducing API calls when moving between variants.

Additional fixed issues:

• Add New Case | When running a case for a kit that previously had an associated PON, case will fail if PON isn’t attached to the kit. This will help mitigate case runs where the DRAGEN version is updated but no new PON is created.

• Edit Case | Fixed a bug resulting in long reanalysis times when only phenotypes were updated in a case.

• Lab Tab | Lab Tab | Fixed a bug resulting in no data loaded to the lab tab for new organizations.

• Analysis Tools | Filters | Fixed a bug for Variant Effect Filters, when moving from simple to advanced, not all variant effects were available for filtering, which also caused a variant count discrepancy.

• Analysis Tools | Preset Filters | Fixed a bug that always showed the description of removing polymorphic variants as ‘Display polymorphism: True’ although the behavior of the filter correctly removed the variants.

• Variant Page | Related Cases | Fixed an issue intermittently causing related cases component to fail to load when moving quickly between variants.

• Export | Fixed a bug failing the export of parental data for some customers.

• Curate | Gene search now excludes variant interpretation paragraphs in order to prioritize gene entity retrieval.

• Settings | Illumina clouds only, ‘See more’ button fixed, it was disabled by v34.4.

V34.5 Update (June 18th, 2024)

• Add New Case | For customers pushing the SNV VCF for DRAGEN 4.2 and 4.0, variants with the targeted tag will be skipped as they cause the pipeline to fail.

• Edit Case | Fixed an issue that failed an edit for cases starting from FASTQ, when new family members were added. The flow of adding family members to an existing case is a supported flow.

• Lab Tab | Fixed an issue where when selecting other family members UI indication of selected sample was unclear due to missing borders on the selection.

• Lab Tab | Fixed an issue that caused average quality percentage to be above 100%.

• Analysis Tools | Presets Schema V2 | Added the possibility to create strictly greater filters on the MQM field to the preset schema.

• Analysis Tools | Filters | Added gnomAD 4.0 GRCh38 MID EAST population to the af_max_any_pop calculation.

• Variant Page | Added the gnomAD 4.0 Mid East exome data to Population Statistics.

• Variant Page | Fixed an issue where when a variant was tagged there was a delay before the auto generated interpretation text was loaded, during which customers may have started to write an interpretation and it was deleted.

• Variant Page | Visualization | Fixed an issue which rarely resulted in an ‘MD5 checksum issue’ error message on the embedded IGV.

• Curate | Gene search now excludes variant interpretation paragraphs in order to prioritize gene entity retrieval.

• Settings | Illumina clouds only, ‘See more’ button fixed, it was disabled by v34.4.

V34.4 Update (May 17th, 2024)

Hotfix released for the following issue:

• Illumina Clouds | Fixed an issue where some users on Illumina clouds could not log into Emedgene. All users must now login using their direct organization URL for their private domain in the Illumina cloud.

V34.3 Updates (May 5th, 2024)

Hotfix released for the following issues:

• Add New Case | Fixed batch case creation issues to re-allow empty sample names and enable upload of validated file.

• Candidate Page | Fixed display of gene in a CNV to match evidence graph gene. Previous fix only covered compound heterozygous variants.

• Variant Interpretation Template | Fixed issue preventing enrichment of template with ACMG classification on V34.

• Export | Fixed an issue preventing export of data from analysis tools if column exceeds csv file limitations. Data will be truncated with a comment.

• Organization Settings | Webhooks | Fixed another issue preventing the trigger of webhooks on cases that transitioned automatically to the ‘Delivered’ status on ILMN clouds.

• Organization Settings | Webhooks | Improved webhook robustness by making webhook statuses case-insensitive, can be capitalized or not.

V34.2 Updates (April 18th, 2024)

Hotfix released for the following 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.

• Pipeline | Pipeline will no longer fail cases with empty VCFs.

• Candidate Page | Fixed issue where displayed gene on candidate page differed from gene in evidence graph/analysis tools.

• Lab Tab | Updated case quality tooltips for increased clarity and accuracy.

• Analysis Tools | Fixed issue where empty evidence graph for Manually Added Variants and large SVs prevented editing of evidence and also caused activity loop.

• Analysis Tools | Fixed issue where multi-select caused extra spacing in table rows.

• Variant Page | Visualization | Improved performance of visualization component.

• Variant Page | Fixed issue where gnomAD mtDNA total AF, homoplasmy count, heteroplasmy count and max AF were erroneously displayed as 0 on the variant page. Preset filters were unaffected by this issue.

• Variant Page | Fixed an issue where MitoTip prediction score quartiles were mislabeled, although the score appears correctly.

• Variant Page to Curate | Fixed an issue where variants curated after initial case run appeared with ‘Export to Curate’ button, instead of ‘Open Curate’.

• Variant Page | Updated Orphanet links to new Orphanet structure.

• Report/Export | Reporting/exporting insufficient coverage regions will now require an organization setting, explicitly selecting only one coverage threshold - 0X, 5X, 10X, 20X, or ALL. This will resolve any issues with reporting insufficient coverage regions.

• Dashboard | Activity Sidebar | Fixed an issue where clicking on a case ID from the activity sidebar did not work.

• Organization Settings | Presets V2 | Improvements to backward compatibility with Presets V1 to enable seamless customer migrations to new tool.

  • Special characters [&, %] allowed in preset name

  • emg_qual_allele_bias and constraint_mis now accept integer or decimal numbers.

  • Any field that accepts a decimal number can now accept a value of 0.

  • Pathogenicity exclusions now includes ClinVar ‘starred_statuses’: ‘criteria provided, conflicting classifications.

• Organization Settings | Webhooks | Fixed an issue where webhooks were not working for the cases ‘Delivered’ status on ILMN clouds.

V34.1 Updates (February 21st, 2024)

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.

• Pipeline | In alignment with DRAGEN recommendations for the SV caller, when variants are larger than 50Kb they will automatically be marked as low quality in order to reduce the number of artifacts shortlisted by the AI and highlighted for review. This affects all DRAGEN versions once a pipeline is updated to v34.

• Pipeline | Added support for multi-allelic CNVs when customers start from joint gVCF.

• Pipeline | Added support for DRAGEN VCFs where hardware is unknown.

• Pipeline | Fixed a bug that caused discordant AI 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 values. This fix will improve pipeline robustness.

• Cases Page | A search on this page will only search for EMG ID, sample names, or any string in the test data. This fix will improve performance.

• Analysis Tools | Fixed intermittent issue causing no variants to load in the variant grid for certain screen sizes and number of variants.

• Analysis Tools | Fixed erroneously generated duplicate and additional columns (e.g. mother_zygosity).

• Analysis Tools | Fixed variant count issue for compound heterozygous filters caused by using a single source for what is essentially a two-step process. Only count displayed was incorrect.

• Analysis Tools | Fixed preset filter issue where presets were returning more results than expected due to ‘-‘ in the gene name in some preset filters. No data was missed.

• Analysis Tools | Fixed issue where ‘greater than’ preset filters also returned a 0 value.

• Analysis Tools | Fixed an issue where after hitting the clear all filters you can no longer save a new preset (refresh was the workaround).

• Analysis Tools | Presets and Preset Groups will include support for some special characters that are in use in legacy presets (e.g. < >).

• Analysis Tools | Preset filters | Clear save error message after correcting the name.

• Analysis Tools | Fixed an issue where variant tagging or pathogenicity changes are not disabled after case is finalized, when multi-select is enabled.

• Organization Settings | Fixed an issue causing available URLs to become unviewable when changing the platform version from V34 to V33.

• Performance: Additional updates to increase performance through infrastructure modifications.

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, Peddy1 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 customers can select their preferred version out of any of the past 5 releases. Customers on 29.0 and below should select an upgrade path at this time.

Updates

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 techsupport@illumina.com.

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.

• Multiselect activity record is for every variant individually, no aggregated activity.

• Mark viewed variants is limited to 5000 variants per user per case, and the API can send 50 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.

1. Apply any filtration strategy using any of the available filters in either simple or advanced mode.

2. 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).

3. 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.

• Delete Preset – Delete a Preset that is not locked and has not been used in a case analysis. Once a Preset has been used in an in-use Preset Group it cannot be deleted, in order to maintain access to the case.

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:

• Select a name (Note: Avoid using non-Latin symbols that don't follow the ISO-5589-1 standard and ‘Default’ and ‘Presets’ are restricted names and cannot be used).

• Add and remove Presets from the Preset Group. A search functionality has been added for ease of use.

• Reorder a list of Presets within the Preset Group.

• Hide/unhide Preset Groups in the table for clear visibility on latest versions available for use. Note that hidden Preset Groups will not affect cases run with them, and when editing a case with a hidden Preset Group it will still be available.

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:

1. Download the JSON file available for the Preset Group in the legacy tab.

2. 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 techsupport@illumina.com, 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 Science 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 PrimateAI and view publications.

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

II. gnomAD v4 is here!

gnomAD v4 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:

1. Gene list threshold: reflects the gene list threshold applied for the case quality check (default: 50).

2. 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.

• Chromosome Validation – Ensures that each chromosome contains a minimum of 1 variant with high quality. 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.

• mtDNA Reference Validation – Ensures that the rCRS reference was used for mtDNA variants. If no mtDNA variants are present in the case the check will receive a Succeed value. Possible values are Succeed, Failed.

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 techsupport@illumina.com 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: 28190455), which calculates a deviation using all the sample alt-alleles, providing a sample specific contamination estimation that can detect human and bacterial 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

• N/A - IDR_BAF = 0.000 or no data is available for this sample (old case)

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

  • Yellow = VUS

  • Red = Pathogenic/Likely Pathogenic

  • Black = Conflicting interpretation of pathogenicity

  • Grey = No assertion provided.

This feature requires an update to Workbench and Pipeline 34.0.

iii. Illumina cloud login improvements that will increase transparency on the selected domain and workgroup. This improves on current state where users are always logged into their previous workgroup regardless of the URL used.

• 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

  • A URL pattern from the list of available patterns

  • A platform version. If a URL is in use with a platform version, only that version will be available for the selected URL.

  • Both the URL pattern and the platform version can be changed from the Organization Settings later.

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 techsupport@illumina.com 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).

• Exports "variant inheritance" – can have several values separated.

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.

• API | No complex sorting via API is possible yet, only on a single column.

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.

• Add New Case | Ordering portal users do not see Network Sharing fields, previously they could see but not edit them.

• Lab Tab, Sidecar | Pedigree | Fixed issue where in very large pedigrees some family members can’t be clicked to view quality.

• Candidates | Fixed a bug when clicking on See all candidates link, variant filters were inactivated.

• Candidates | Fixed issue where SV Insertions information was partially displayed.

• Variant Page | Visualization | Fixed an UI issue where IGV window was out of frame.

• Variant Page | ACMG SNV Score | Fixed but where incorrect score was showing for mtDNA variants, although classifier behaves as expected.

• Variant Page | Fixed issue where zygosity can’t be edited in the Sanger confirmation component.

• Cases Page | Fixed issue where contact support link for failed cases did not work.

• Report/Export | Fixed issue where variants tagged as ‘Most Likely’ order was not preserved when pushing to the report.

• Report/Export | Fixed issue in miniVCF header blocking subsequent analysis in other tools.

• Activity | Fixed issue where long names were not displayed properly.

• Pipeline | Multiple improvements to avoid pipeline failures due to unavailable files and resources.

• Infrastructure | Multiple improvements of resource allocations to increase robustness and performance.

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.

• Add New Case | Test type ‘Other Test’ is not supported on Illumina clouds yet.

• 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.

• Reanalysis | If HPO terms were updated between analyses, the reanalysis will not automatically map previous HPO terms to new ones.

• Lab Tab | Reanalyzed cases will show up with duplicated insufficient gene regions.

• Lab Tab | STR repeats number for parents does not exist, proband values displayed.

• Lab Tab | Insufficient coverage export will not work via UI or API if an included gene does not have a start or end position in NCBI.

• Candidates | Gene name displayed on candidate page can be different than pipeline and variant Page.

• Candidates Page | Compound het SNV-CNV variants will not display the automated CNV classification. Workaround – view variants from analysis table.

• Evidence Graph | LitVar links will not work due to a change in the LitVar link structure.

• Variant Page | Clinical Significance | When a disease has both an OMIM and a CGD source, the CGD inheritance modes mistakenly override OMIM inheritance modes.

• Variant Page | Visualization | Chromosome ideogram visualization is missing for mtDNA variants in VCF case run on GRCh37.

• Variant Page | Visualization | Simple/Advanced selectors will not work for locally uploaded BAM files.

• Variant Page | Visualization | Zoom out of BigWig/TTS displays mean data.

• Variant Page | Visualization is not supported for users storing VCF and CRAM on ICA V1 and BSSH. Only VCF and BAM are supported.

• Variant Page | Manually Added Variants | Users without the role can add variants but not save them. Button should be disabled.

• Variant Page | Transcript selection in fusion genes may be blocked since only a transcript for a single gene can be selected.

• Analysis Tools | Preset Filters | Preset containing a gene list ID will display filtered data when an organization has configured a base gene list filter.

• Analysis Tools | ‘Last’ button on pagination does not work.

• Organization Settings | Set mandatory fields - does not work from the UI. Please contact support if you’d like to configure these fields for your account.

• Organization Settings | Gene Lists | Very large gene lists (>6700 genes) may return a false error message during creation, despite being successfully created.

• Network | 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 section] shows relevant information. Same gap for manually classified variants.

• Network | 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.

• ILMN Clouds | Help Center | Some links may not work. Work around: Paste the title into the help center search.

• Curate | ILMN cloud users need to be logged in to the organization from which they are trying to access Curate.

• Curate | Discrepancy between Analyze and Curate HGVS parser may be experienced.

• API | Assign users to case fails with no error if faulty emails used.

• API | Creation of large gene lists may return an error (due to timeout) despite the creation of the gene list.

• API | Marking over 5000 variants as viewed will not result in an error message, although this is the database limitation for saving viewed variants.

• API | Swagger | Authorize function returns a 400 error.

• Webhooks | Not functioning for software case status changes.

• Activity | Editing interpretation paragraph yields an erroneous activity labeled reanalysis.

• Dashboard | Diagnostic Yield includes Uncertain as Resolved.

Version update needed for access to new features

References

1. 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), http://dx.doi.org/10.1016/j.ajhg.2017.01.017