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Nat Genet. 2020 Jan;52(1):35-39. doi: 10.1038/s41588-019-0560-2. Epub 2019 Dec 23.

GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize disease candidate genes.

Author information

1
School of Computer Science, University of Manchester, Manchester, UK.
2
School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
3
School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
4
School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. m.tassabehji@manchester.ac.uk.
5
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK. m.tassabehji@manchester.ac.uk.

Abstract

With large-scale population sequencing projects gathering pace, there is a need for strategies that advance disease gene prioritization1,2. Metrics that provide information about a gene and its ability to tolerate protein-altering variation can aid in clinical interpretation of human genomes and can advance disease gene discovery1-4. Previous reported methods analyzed the total variant load in a gene1-4, but did not analyze the distribution pattern of variants within a gene. Using data from 138,632 exome and genome sequences2, we developed gene variation intolerance rank (GeVIR), a continuous gene-level metric for 19,361 genes that is able to prioritize both dominant and recessive Mendelian disease genes5, that outperforms missense constraint metrics3 and that is comparable-but complementary-to loss-of-function (LOF) constraint metrics2. GeVIR is also able to prioritize short genes, for which LOF constraint cannot be estimated with confidence2. The majority of the most intolerant genes identified here have no defined phenotype and are candidates for severe dominant disorders.

PMID:
31873297
DOI:
10.1038/s41588-019-0560-2

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