MutationTaster2021

Abstract

Here we present an update to MutationTaster, our DNA variant effect prediction tool. The new version uses a different prediction model and attains higher accuracy than its predecessor, especially for rare benign variants. In addition, we have integrated many sources of data that only became available after the last release (such as gnomAD and ExAC pLI scores) and changed the splice site prediction model. To more easily assess the relevance of detected known disease mutations to the clinical phenotype of the patient, MutationTaster now provides information on the diseases they cause. Further changes represent a major overhaul of the interfaces to increase user-friendliness whilst many changes under the hood have been designed to accelerate the processing of uploaded VCF files. We also offer an API for the rapid automated query of smaller numbers of variants from within other software. MutationTaster2021 integrates our disease mutation search engine, MutationDistiller, to prioritise variants from VCF files using the patient's clinical phenotype. The novel version is available at https://www.genecascade.org/MutationTaster2021/. This website is free and open to all users and there is no login requirement.

Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

“…In gnomAD, the LEP gene (canonical transcript ENST00000308868.4) was analysed and data pertaining to non-synonymous and LoF variants as well as the corresponding populationspecific allele counts, and frequencies were extracted. Consequences on the leptin protein by non-synonymous variants were predicted utilizing various in silico tools, namely Sorting Intolerant From Tolerant (SIFT, 19), Polymorphism Phenotyping v2 (PolyPhen2, 20), MutationTaster2021 (21), Functional Analysis through Hidden Markov Models -multiple kernel learning (FATHMM-MKL, 22) and Protein Variation Effect Analyzer (PROVEAN, 23). Predictions by SIFT, FATHMM-MKL and PROVEAN were obtained with the help of the Variant Effect Predictor (VEP, 24).…”

“…S1 Table: Summary of the results of the in silico analyses of LEP variants deposited in gnomAD. Supplementary Table S1 represents the in silico predictions for each variant present in all populations by various tools, namely SIFT (19), PROVEAN (23), PolyPhen2 (20), MutationTaster2021 (21) and FATHMM-MKL (22). The tools are ordered by their reported accuracy (left: highest accuracy; right: lowest accuracy; 27).…”

TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis

“…broadinstitute. org/), predicted pathogenicity using functional prediction tools including CADD, 35 MutationTaster 36 and other prediction tools as appropriate; ensuring inclusion of previously reported disease associated SNPs. Structural variation will also be examined.…”

Structure-Based Understanding of ABCA3 Variants

“…Variant allelic frequency was obtained from gnomAD v2.2.1 (Genome Aggregation Database) and their clinical significance was reported from ClinVar (1 May 2021 release). In silico prediction of pathogenicity was evaluated with: SIFT 6.2.0 (http://sift.jcvi.org/; Bioinformatics Institute, Singapore, accessed on 14 May 2021), PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/, Cambridge, MA, USA, accessed on 14 May 2021), MutationTaster2 (http://www.mutationtaster.org/, Charité Berlin, Germany, accessed on 14 May 2021) [33], CADD score (CADD v1.6 (https: //cadd.gs.washington.edu/snv, University of Washington, Seattle, WA, USA, Hudson-Alpha Institute for Biotechnology, Huntsville, AL, and Berlin Institute of Health, Germany, accessed on 14 May 2021) [34], Varsome (https://varsome.com/, Saphetor SA, Switzerland, accessed on 12 May 2021) [35] and Intervar (http://wintervar.wglab.org/, Wang Genomic Lab, Philadelphia, PA, USA, accessed on 12 May 2021) [36].…”