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Cited by 12Genomics and Rare DiseasesGenetic Associations and EpidemiologyCancer Genomics and Diagnostics

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DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features

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Luppino, Federica, Adzhubei, Ivan A., Cassa, Christopher A., Toth-Petroczy, Agnes·2023·Nature Communications
DOI 10.1038/s41467-023-37661-zPMC PMC10115847

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Abstract

Despite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) provide valuable evidence in variant assessment, but they are prone to misclassifying benign variants, contributing to false positives. Here, we develop Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for missense variants trained using extensive diagnostic data available in 59 actionable disease genes (American College of Medical Genetics and Genomics Secondary Findings v2.0, ACMG SF v2.0). DeMAG improves performance over existing VEPs by reaching balanced specificity (82%) and sensitivity (94%) on clinical data, and includes a novel epistatic feature, the ‘ partners score’, which leverages evolutionary and structural partnerships of residues. The ‘partners score’ provides a general framework for modeling epistatic interactions, integrating both clinical and functional information. We provide our tool and predictions for all missense variants in 316 clinically actionable disease genes (demag.org) to facilitate the interpretation of variants and improve clinical decision-making.

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Metadata

Authors
Luppino, F., Adzhubei, I. A., Cassa, C. A., & Toth-Petroczy, A.
Affiliations
  • Center for Systems Biology Dresden (DE)
  • Brigham and Women's Hospital (US)
Corresponding author
Cassa, Christopher A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-04-19
Volume
14
Issue
1
Pages
2230-2230
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-37661-z
PMC
PMC10115847
OpenAlex
W4366405805
Cited by
12
References
5
Citations by year
2026: 3 · 2025: 5 · 2024: 4
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Max-Planck-Gesellschaft (MPRGL)
  • U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (R01-HG010372)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
variant effect prediction, missense mutations, variants of uncertain significance, epistasis, protein structure, evolutionary conservation, variant interpretation
MeSH terms
Genetic Testing, Humans, United States, Genetic Variation, Mutation, Missense, Genomics

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