Inferring the molecular and phenotypic impact of amino acid variants with MutPred2.

Nature Communications
Vikas PejaverPredrag Radivojac

Abstract

Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants.

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Citations

Jan 10, 2021·Animal Genetics·Samantha L Van BurenKatie M Minor
Feb 13, 2021·Genes·Anna LetkoAlexander Grahofer
Mar 7, 2021·Genes·Brais Bea-MascatoDiana Valverde
Apr 6, 2021·Frontiers in Molecular Biosciences·Yannick MahlichYana Bromberg
May 11, 2021·Animal Genetics·H BeauvoisM Abitbol
May 14, 2021·Journal of Biomolecular Structure & Dynamics·Insan HabibMd Imtaiyaz Hassan
Jun 3, 2021·Genes·Matthias ChristenDaniel Sanchez-Masian
May 25, 2021·Frontiers in Molecular Biosciences·Sundeep Chaitanya VedithiTom L Blundell
Jul 20, 2021·Journal of Biomolecular Structure & Dynamics·Samadrita ChatterjeeYasha Hasija
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Nov 4, 2021·Briefings in Bioinformatics·Fuyi LiJiangning Song

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Methods Mentioned

BETA
exome sequencing
two-hybrid
PCR
Y2H

Software Mentioned

PhyloP
HumVar
PolyPhen
HIT
SwissVar
ClinVar
ANNOVAR
CD
HumDiv
SIFT

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