Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,773 bioRxiv papers from 265,845 authors.

Using high-resolution variant frequencies to empower clinical genome interpretation

By Nicola Whiffin, Eric Minikel, Roddy Walsh, Anne O'Donnell-Luria, Konrad Karczewski, Alexander Y Ing, Paul J. R. Barton, Birgit Funke, Stuart A Cook, Daniel MacArthur, James S Ware

Posted 02 Sep 2016
bioRxiv DOI: 10.1101/073114 (published DOI: 10.1038/gim.2017.26)

Whole exome and genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognised as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants. Here we present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets. Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, and identifies 43 variants previously reported as pathogenic that can now be reclassified. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

Download data

  • Downloaded 4,340 times
  • Download rankings, all-time:
    • Site-wide: 488 out of 57,773
    • In genomics: 130 out of 4,057
  • Year to date:
    • Site-wide: 5,275 out of 57,773
  • Since beginning of last month:
    • Site-wide: 7,286 out of 57,773

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News