Title: Missense Loss-of-Function variation: increased resolution for analysis of functional constraintMissense Loss-of-Function variation: increased resolution for analysis of functional constraint

Abstract: Understanding the functional effects of genetic variation identified through genome sequencing is an unsolved problem.  Not least because this has consequences for clinical interpretation of human genomic variation.  We have developed a method to use predictions of variation-induced protein instability to identify missense variation that may have functional consequences.  In my talk I will present this technique for predicting missense loss-of-function variation, and how this data type allows greater resolution for measuring functional constraint of individual genes.  Application of this method requires less genomic data than previously, opening the possibility of reliable LOEUF scores from disease cohorts and even non-human species.