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Response to Shah et al: Using high-resolution variant frequencies empowers clinical genome interpretation and enables investigation of genetic architecture

By Nicola Whiffin, Angharad M. Roberts, Eric Vallabh Minikel, Zach Zappala, Roddy Walsh, Anne H. O’Donnell-Luria, Konrad Karczewski, Steven M. Harrison, Kate L Thomson, Helen Sage, Alexander Y Ing, Paul JR Barton, Stuart A. Cook, Daniel G MacArthur, James S Ware

Posted 06 Aug 2018
bioRxiv DOI: 10.1101/384271

Recent work by Shah and colleagues demonstrated that many variants in the ClinVar database are misclassified, and that disease-specific allele frequency (AF) thresholds can identify wrongly classified alleles by flagging variants that are too prevalent in the population to be causative of rare penetrant disease. While we agree with the main conclusions of this work, the authors compare their AF filtering approach to our recently published method, concluding that the method we advanced 'may be prone to removing potentially pathogenic variants'. This is incorrect. Here we demonstrate that our approach is robust, and further illustrate the power of disease-specific AF thresholds for investigating the genetic architecture of disease.

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