Key New Features

• ACMG classification amended to use a points based score.

• All in-silico scores have been calibrated per ClinGen guidelines.

• MANE Select & MANE Plus transcripts displayed and used in ACMG.

Additional Features

• Drug information from the Precision Medicine Knowledge Base (PMKB) is incorporated in the AMP classifier.
• Additional data included from Drug-Gene Interactions (DGI) displayed.
• BLOSUM score is displayed for missense variants.
• Continual improvements and a few bug fixes.

Please note: These new features will not be immediately included on the VarSome Clinical platform. Once we have received feedback for our points based improvements to the ACMG classifier we will then release these relevant features to VarSome Clinical. 

New Features

ACMG implementation of recent ClinGen guidelines

This release includes a major update to our ACMG classifier, implementing recent ClinGen guidelines:

1. PM2: Recommendation for Absence/Rarity Criterion PM2 (Version 1.0)
2. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines
3. PP3/BP4: Evidence-based calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations

1. PM2: Recommendation for Absence/Rarity Criterion PM2 (Version 1.0)

The weight of Criterion PM2 (“Absent from controls, or at extremely low frequency if recessive”) will now only ever be triggered with strength “Supporting” instead of “Moderate”. 

2. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines

We have implemented the proposed points-based system for evaluating the ACMG verdict, the points represent a log-scale of the odds of a variant being pathogenic (or benign) as follows:

• Supporting = 1 point
• Moderate = 2 points
• Strong = 4 points
• Very Strong = 8 points

A total score is computed as sum(pathogenic evidence) - sum(benign evidence) and the following thresholds applied:

• Pathogenic if >= 10
• Likely Pathogenic if >= 6
• Uncertain if >= 0
• Likely Benign if >= -6
• Benign if <= -7

This is a very straightforward system that is clear and unambiguous. It also makes it possible to measure whether any individual rule and strength is exceeding, or failing to meet, the level of evidence required.

3. PP3/BP4: Evidence-based calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations

ACMG have proposed an evidence-based method of calibrating all in-silico predictors, comparing them to ClinVar data. We have used this to calibrate over 30 in-silico predictors, giving us an objective measure and rank of the accuracy of individual predictors. As a result, we have selected:

• BayesDel_addAF for missense variants
• CADD (VarSome Premium) for truncating / non-coding variants
• DANN for non-VarSome Premium users
• scSNV for splice-site prediction
• phyloP100Way for conservation

VarSome will now display in-silico predictions using these new scores presenting a graduated response:

Rules PP3 (Multiple lines of computational evidence support a deleterious effect on the gene or gene product) and BP4 (Multiple lines of computational evidence suggest no impact on gene or gene product) will now trigger with varying strengths.

4. Impact

As a result of these changes, VarSome’s ACMG classifier adheres more closely to the guidelines, calls pathogenic variants with greater confidence, and pushes more uncertain variants into the 'Likely Benign' category.

MANE Transcripts and MANE in ACMG

The MANE project (Matched Annotation from the NCBI and EMBL-EBI) aims to define a set of representative transcripts for all human protein-coding genes. Each MANE transcript represents an exact match in exonic regions between a Refseq transcript and its counterpart in the Ensembl/GENCODE annotation. 

This release sees the introduction of MANE Select and MANE Plus within VarSome.

These data are presented as new columns in the Transcripts table. Additionally, for Ensemble, we have included APPRIS and UniProt accession.

In addition MANE is now used in the ACMG classifier. Previously the classifiers gave precedence to canonical but now precedence is given in the following order:

MANE select > Canonical > MANE Plus

The transcript used in classification is highlighted in the Transcripts summary card.

For detailed information on the aims and purpose of the MANE project please follow the information link.

AMP Classification

PMKB

The Precision Medicine Knowledge Base (PMKB) is now used to improve the AMP classification when a drug entry is available. .

It is used in the 'Drugs and Treatments Tier' verdict by leveraging available drugs.  

 Or Tier IV if no information is found not found. 

Further information can be found here. 

DGI

The DGI component has been updated. By clicking on the “More Details” option we now display additional information  about the selected drug. 

Note: The full AMP classifier is only available to VarSome Premium and VarSome Clinical users. VarSome Clinical users also benefit from the inclusion of additional licensed databases such as JAX CKB and COSMIC.

Pathogenicity Scores

New In-Silico Thresholds

All in-silico scores are now coloured by pathogenicity using the newly computed thresholds. The original raw prediction is displayed but not tallied in the bar chart above.

Full details & thresholds are available here.

BLOSUM

The BLOSUM score ( (BLOcks SUbstitution Matrix)  has been added to the Pathogenicity Scores when viewing missense SNVs. The score is coloured pathogenic if <= -4, and benign if >= 0, otherwise it is classified as Uncertain.

hg38/hg19 Lift-over

Variants described using chromosome & position can now be lifted over between hg19 and hg38 or vice-versa:

Further Information and Support

Not already a VarSome Premium, VarSome API or VarSome Clinical user? Get in touch and ask for a free trial.

As ever we hope you find these changes and improvements helpful, we’d love to hear any suggestions you may have, support is available as usual from support@varsome.com

- The VarSome Team