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. 2017 Jan 16;18(1):6.
doi: 10.1186/s13059-016-1141-7.

GAVIN: Gene-Aware Variant INterpretation for Medical Sequencing

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Free PMC article

GAVIN: Gene-Aware Variant INterpretation for Medical Sequencing

K Joeri van der Velde et al. Genome Biol. .
Free PMC article

Abstract

We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated deleteriousness based on CADD scores for >3000 genes. In a benchmark on 18 clinical gene sets, we achieve a sensitivity of 91.4% and a specificity of 76.9%. This accuracy is unmatched by 12 other tools. We provide GAVIN as an online MOLGENIS service to annotate VCF files and as an open source executable for use in bioinformatic pipelines. It can be found at http://molgenis.org/gavin .

Keywords: Allele frequency; Automated protocol; Clinical next-generation sequencing; Gene-specific calibration; Pathogenicity prediction; Protein impact; Variant classification.

Figures

Fig. 1
Fig. 1
Performance of GAVIN and other tools across different clinical gene sets. Prediction quality is measured as sensitivity and specificity, i.e. the fraction of pathogenic variants correctly identified and the fraction of misclassifications/non-classifications while doing so
Fig. 2
Fig. 2
Comparison of gene-specific classification thresholds with genome-wide fixed thresholds in three groups of genes: 737 genes for which CADD is predictive, 684 genes for which CADD is less predictive, and 766 genes with scarce training data. For each group, 10,000 sets of 100 benign and 100 pathogenic variants were randomly sampled and tested from the full set of 25,765 variants and accuracy was calculated for gene-specific and genome-wide CADD and MAF thresholds

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References

    1. Berg JS, Khoury MJ, Evans JP. Deploying whole genome sequencing in clinical practice and public health: Meeting the challenge one bin at a time. Genet Med. 2011;13:499–504. doi: 10.1097/GIM.0b013e318220aaba. - DOI - PubMed
    1. Cooper GM, Shendure J. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Nat Rev Genet. 2011;12:628–40. doi: 10.1038/nrg3046. - DOI - PubMed
    1. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5. doi: 10.1038/ng.2892. - DOI - PMC - PubMed
    1. van der Velde KJ, Kuiper J, Thompson BA, Plazzer JP, van Valkenhoef G, de Haan M, et al. Evaluation of CADD scores in curated mismatch repair gene variants yields a model for clinical validation and prioritization. Hum Mutat. 2015;36:712–9. doi: 10.1002/humu.22798. - DOI - PMC - PubMed
    1. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81. doi: 10.1038/nprot.2009.86. - DOI - PubMed

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