--- title: Our ACMG Classifier Is About To Get Even Better description: We will be implementing a points-based score and new in-silico thresholds which will reduce number of VUS with a small reduction in sensitivity and an increase in specificity. image: https://updates.varsome.com/hubfs/GV_1200x628_ClinicalResearch.jpg --- [![VarSome](https://updates.varsome.com/hubfs/VarSome_February2020%20Theme/Images/logo.png)](https://varsome.com/) - Editions - [More about VarSome.com](https://varsome.com/varsome-editions/varsome/) - [More about VarSome Premium](https://varsome.com/varsome-editions/varsome-premium/) - [More about VarSome Clinical](https://varsome.com/varsome-editions/varsome-clinical/) - [Learn more about APIs](https://varsome.com/information/varsome-api-info/) - About - Resources - [Library](https://varsome.com/library/) - [Documentation](https://docs.varsome.com/) - [Query types](https://varsome.com/about/examples/) - [IVDR](https://landing.varsome.com/ivdr-whitepaper) - [Germline Classification](https://varsome.com/about/resources/acmg-implementation/) - [Somatic Classification](https://varsome.com/about/resources/amp-implementation/) - Partners - [Distributors](https://varsome.com/distributors/) - [Partners](https://varsome.com/partners/) - [Become a partner](https://landing.varsome.com/become-varsome-partner) - General - [The Company](https://saphetor.com/about/) - [Cite VarSome](https://varsome.com/about/varsome-citations/) - [Link to VarSome](https://varsome.com/how-do-i-create-link-varsome/) - [Contact](https://landing.varsome.com/contact) - [Community](https://varsome.com/community-contributions/) - [Blog](https://blog.varsome.com/) [Platform Updates](https://updates.varsome.com/en/tag/platform-updates) [VarSome.com](https://updates.varsome.com/en/tag/varsome-com) [VarSome.com Premium](https://updates.varsome.com/en/tag/varsome-com-premium) [ACMG](https://updates.varsome.com/en/tag/acmg) # Our ACMG Classifier Is About To Get Even Better By [Carl Smith](https://updates.varsome.com/en/author/carl-smith) on September, 8 2022 ### Categories - Select a Topic - [All](https://updates.varsome.com/en) - [Platform Updates](https://updates.varsome.com/en/tag/platform-updates) - [VarSome Clinical](https://updates.varsome.com/en/tag/varsome-clinical) - [VarSome API](https://updates.varsome.com/en/tag/varsome-api) - [Release](https://updates.varsome.com/en/tag/release) - [VarSome.com Premium](https://updates.varsome.com/en/tag/varsome-com-premium) - [VarSome.com](https://updates.varsome.com/en/tag/varsome-com) - [ACMG](https://updates.varsome.com/en/tag/acmg) ### Stay up to date ##### Search The Blog [Back to main Blog](https://updates.varsome.com/en) ![](https://app.hubspot.com/settings/avatar/409171fee064910b6bf04363a7781f22) ###### Carl Smith In late September, we will be introducing a significant upgrade to our ACMG Classifier. In line with recent ClinGen guidelines, we will be implementing a points-based score which will reduce the number of variants classified as ‘VUS’, by reducing sensitivity and increasing specificity. This will, initially, be deployed on VarSome.com. A subsequent roll out to VarSome Clinical will take place once we have received and addressed feedback from our users. # Overview The growing adoption of next generation sequencing (NGS) in clinical laboratories over the past decade resulted in the development of standardized guidelines for the interpretation of genetic data. The American College of Medical Genetics and Genomics (ACMG) developed standard terminology for the classification of variants identified in Mendelian disorders; ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’. They also [recommended a process](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544753/) that would allow clinicians and researchers to assess available evidence to confidently allocate one of these categories to their variants.    Examining and interrogating the available evidence is a lengthy manual process, involving querying numerous data sources and in silico prediction tools. This bottleneck is what [VarSome](https://varsome.com/) was built to address. Rather than needing to have a library of tabs open, researchers and clinicians can view [140 data sources](https://varsome.com/datasources/) in one place giving them an easy to read [overview of available evidence](https://updates.varsome.com/en/varsome-11.2.6-cards-view) for their variant of interest. The VarSome team also developed an algorithm to [automatically apply ACMG’s interpretation criteria](https://varsome.com/about/resources/acmg-implementation/) across the aggregated database to classify variants based on the ACMG terminology.   Since the implementation of [VarSome’s ACMG classifier](https://landing.varsome.com/implementation-of-acmg-guidelines-whitepaper), it has become a ubiquitous tool trusted by research and clinical laboratories around the world to power variant interpretation pipelines.   In the coming weeks we will be releasing a major update to our ACMG classifier. This update implements several recent [ClinGen guidelines](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/):   1. [PM2: Recommendation for Absence/Rarity Criterion PM2 (Version 1.0)](https://clinicalgenome.org/docs/pm2-recommendation-for-absence-rarity/) 2. [Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines](https://clinicalgenome.org/docs/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](https://clinicalgenome.org/docs/evidence-based-calibration-of-computational-tools-for-missense-variant-pathogenicity-classification-and-clingen-recommendations/) The impact of these implementations is that we will have a lower sensitivity and higher specificity. As a result, the overall number of called variants of ‘uncertain significance’ will decrease in favor of an increase in ‘benign’ variants. # Implementation of recent ClinGen guidelines ### 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 are implementing 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](https://clinicalgenome.org/docs/evidence-based-calibration-of-computational-tools-for-missense-variant-pathogenicity-classification-and-clingen-recommendations/) 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](https://landing.varsome.com/varsome-premium)) for truncating / non-coding variants - **DANN** for non-[VarSome Premium](https://landing.varsome.com/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: ![](https://lh3.googleusercontent.com/h67mg8TV8QdAiz3SiMAdQuaRgdY-NjP21cep7wiHTGW2koFuT-COIEqLzPRRfe0JC30Nm2WZOWjtu7hhCdK4n7edhAaRaFrNXPDuMGqVsQ-MaYx-0-oU3ZxW2hTDsQPJRhRfw_a6imYMbQbZ8ACNUI3Gq9wrkvQgnvz4GijMbEGLwiWsEVxT9fjK6g)![](https://lh5.googleusercontent.com/EcV8pvi-PhCsgQ0-_HhHzM5P_rzypwyal2CXWsc10Gfx6XyRJPhFNDhTVwSo0nuUxgiRMSRW0EjEzuxX7-5IbxFQmcY7XfU9DqlVokoxoBfsq5EtTJh--yxFlQU79brcQ_WFXGjqSGbv5e9aIL82dA43rkGM23WJwGX2zIz-sXE5ejmoSDNdnHOdMQ) 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. # Further information A more detailed explanation of the changes will be provided in the accompanying release note of VarSome 11.4, which will be released in mid to late September. This update will only apply to the [VarSome](https://varsome.com/), [VarSome Premium](https://landing.varsome.com/varsome-premium) and [VarSome API](https://landing.varsome.com/varsome-api) ACMG classification tool through which we will gather feedback before deploying to [VarSome Clinical](https://landing.varsome.com/varsome-clinical).   If you have any questions or comments regarding the upcoming improvements to the ACMG classifier, we are always happy to [hear from you](mailto:support@varsome.com). [Previous Post](https://updates.varsome.com/en/varsome-api-update-v-11.3.10) [Next Post](https://updates.varsome.com/en/use-of-clinical-evidence-in-varsomes-acmg-implementation) #### Submit a Comment ### Stay up to date ## Latest News [See all blog posts](https://blog.varsome.com) ![](https://updates.varsome.com/hubfs/VarSome_February2020%20Theme/Images/logo.png) - VarSome Suite - [VarSome.com](https://saphetor.com/varsome-editions/varsome/) - [VarSome Premium](https://saphetor.com/varsome-editions/varsome-premium/) - [VarSome Clinical](https://saphetor.com/varsome-editions/varsome-clinical/) - [VarSome API](https://varsome.com/information/varsome-api-info/) - System Status - [System Status](http://status.saphetor.com/) - Resources - [Query Examples](https://varsome.com/about/examples/) - [Documentation](https://docs.varsome.com/) - [Help Center](https://docs.varsome.com/en) - [Cite VarSome](https://news.varsome.com/en/cite-varsome-the-human-genomic-variant-search-engine) - The Company - [About Saphetor SA](https://saphetor.com/about/) - [News](https://blog.varsome.com) - [Distributors](https://landing.varsome.com/distributors) - [Contact](https://saphetor.com/contact/) - Legal - [Terms of Use](https://varsome.com/terms/) - [Privacy Policy](https://varsome.com/privacy/) VarSome Suite is brought to you by [Saphetor SA](https://saphetor.com). © 2024 Saphetor SA – All Rights Reserved.