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 customers 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

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

  • Variant interpretation

  • Gene-related disease (unless it is custom)

  • Selected transcript (unless it is custom)

  • ACMG data (classification, score, tags, tag strength, tag notes)

• Open: If the variant is already in your Curate database you will also see an “Open” in Curate button, which is also the behavior in versions under V38.

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.

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

• Population frequency of LoF variants in the same exon

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)

• Phenotype not consistent with gene (0,0)

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 sections 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 version 113. 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’.

<figure><img src="../../.gitbook/assets/qual.png" alt=""><figcaption></figcaption></figure>

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.

<figure><img src="../../.gitbook/assets/multitag.png" alt="" width="375"><figcaption></figcaption></figure>

• 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

• Create a new gene

• Search for a gene by HGNC ID

• Update an existing gene

• Export all variants and genes

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.

• Add New Case | Adding metrics.tar.gz files is not supported from BSSH.

• Add New Case | API/Batch/UI discrepancies:

  • Cannot add phenotypes for unaffected parent in batch upload

  • Cannot use the same gVCF file for multiple samples from the UI

  • No validation for sample name in array JSON from batch upload/API

• Add New Case | BSSH | Human readable BSSH paths in batch upload do not work for customers with large BSSH accounts. Patch planned for late May.

• Add New Case | File name can be at most 255 characters.

• Candidates, Variant Page, Curate | Evidence graph & ACMG automation will not be calculated for CNVs over 20MB. They will not have a gene related disease card in Curate.

• Lab Tab | Peddy contamination calculations may be inaccurate for panels due to small number of variants.

• Genome View | Only the largest 500 variants are displayed.

• Analysis Tools | Manually Added Variants | STRs | Format is not aligned with format of STRs on the software, e.g. missing variant length.

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

• Analysis Tools | Filters | ACMG pathogenicity filters don’t support CNVs.

• Analysis Tools | Presets | Preset filters v1 schema is deprecated, please upgrade to V2 prior to moving to any version over 37.

• Analysis Tools | Custom Presets & Settings | Presets – Cannot save custom and preset filters with {} in name.

• Analysis Tools | Search for CNVs by position does not consider end, only start.

• Candidates, Variant Page | After editing the evidence graph, phenotypic match strength indications are missing from the sidecar and variant page.

• Candidates | Evidence Graph | Changing the disease in the evidence graph will not automatically change the inheritance mode, that needs to be manually edited as well.

• Variant Page | Max AF in the analysis tools and export is across population DBs; the gnomAD card displays a different Max AF, referring only to gnomAD data.

• 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.

• Webhooks | Cannot be trigger on internal software statuses such as ‘In Progress’ ‘Reanalysis’.

• Reporting | PMIDs will only work if there is an author on link, no support for books.

• Export to excel is limited to 32KB per cell, which may prevent exports with very large CNVs.

• Organization Settings | BED upload | Validation on the UI component does not check the following. No validation at all for API uploads.

  • All lines in the BED must contain the same number of columns

  • No duplicate lines

  • No trailing whitespaces

  • No validation on ChrM

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

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.

• Add New Case, Edit Case | The virtual panel, boosted gene, carrier analysis selector is clickable on the entire row and not just the radio button and text.

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

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

• Cases Page | Illumina Clouds | Users that have been removed from workgroups in IAM can still be added as participants to a case. They will not have access to the software, and there is no security/access risk.

• Cases Page | Reupload fails for JSON files.

• 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.

• Lab Tab | When a gene is removed from the knowledge graph, no coverage will be shown, unless gene is removed from gene list.

• Lab Tab | Open in IGV desktop only works if case has been previously linked to IGV desktop from the analysis tools. The feature is not working at all in V37+, scoped into the June or July patches.

• Lab Tab | % BP calculation can be slightly and rarely misleading due to pipeline rounding calculation to two decimal points.

• Analysis Tools | Search | Searching for ‘chromosome: position ref > alt’ is not yet implemented for CNVs.

• Analysis Tools | gnomAD allele frequency rounding inconsistent with Variant Page rounding which is to 4 digits.

• Analysis Tools | Filters | Not all AI modes are available for filtering in Evidence & Tags, advanced mode. Missing Carrier Analysis and Incidental.

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

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

• Variant Page | Summary Tab | gnomAD AF, Max AF and hom/hemi counts for SV INS variants are missing from summary tab but available in Population Statistics section.

• Variant Page | Gene-related disease & Evidence Graph | For CNVs, editing the gene-related disease does not change in evidence graph despite a warning message that it will.

• Variant Page | Clinical Significance | Gene-related disease component shows matching/unmatching disease phenotypes, but can also show patient phenotypes erroneously.

• Variant Page | Clinical Significance | For reanalyzed cases, network classified variants may appear as N/A for cases on GRCh38.

• Variant Page | Quality | Allele distribution chart for reference variants does not work for non-proband case members.

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

• Variant Page | Visualizations | Curate link isn’t working for Curate track variants.

• Variant Page | Population Statistics does not display mtDNA organization DBs even when the case is correctly annotated with the data.

• Variant Page | Connected Variants | Some compound heterozygous connections spanning multiple genes might not be shown in component. They will be captured in filters.

• Variant Page | Related Cases | Not working as expected for SV insertions.

• 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 | When manually changing a tag status from inactive to active and back again, tag status might be incorrect.

• Variant Page | ACMG Automation | Evidence is missing Emedgene auto-calculation icon when user makes a change.

• Variant Page | Load to desktop IGV not working for ClinVar SV file.

• Report | Download button is not visible in the User Interface in V37+, although the download is still available.

• Curate | Searching for a variant causes the related cases to disappear even when search is removed. Work around is to refresh.

• Curate | Large CNVs do not have a gene-related disease card even if a gene related disease appears in Analyze.

• Curate | Orphanet link structure has changed and does not work in Curate (fixed in Analyze).

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

• Settings | Editing preset filters, please edit filters one by one and save each. Batch editing can result in filters combining.

• Organization Settings | API Gene Lists | Does not support NCBI only export/import. This is supported from the UI.

• Organization Settings | Gene Lists | For organizations with thousands of gene lists, UI component might time out occasionally.

• Organization Settings | Setting analysis column order, some columns are missing: AI rank, Variant length, Manual classification, Network classification, Historic AF %, Historic AF #, Noise AF %, Noise AF #.

• 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.

• Dashboard | Diagnostic Yield includes Uncertain as Resolved.