Genetic diagnosis is the cornerstone of genomic medicine for Mendelian disorders. It aims to identify one or a handful of causal variants in a patient's genome based on the wealth of sequence, functional, and clinical data. However, a variant's classification as pathogenic and benign is conditioned on the lines of available evidence supporting or refuting its disease causality. These lines of evidence are specified in the ACMG/AMP guidelines that designate evidential type, strength, and direction, and include a set of deterministic rules for combining evidence to classify a variant. In this talk, we will focus on missense variants and describe our approaches towards calibrated variant classification using computational predictors, population variation and high-throughput functional assays. We compute the posterior probability of pathogenicity for each evidence type and subsequently combine them using a point-based system. We will demonstrate that the new quantitative criteria improve variant classification and discuss potential problems with dependencies and circularity in the system.

Predrag Radivojac is a Professor of Computer Science at Northeastern University. He received his Bachelor's and Master's degrees in Electrical Engineering from the University of Novi Sad and University of Belgrade, Serbia. His Ph.D. degree is in Computer Science from Temple University under the direction of Prof. Zoran Obradovic and co-direction of Prof. Keith Dunker. In 2004 he held a post-doctoral position in Keith Dunker's lab at Indiana University School of Medicine, after which he joined Indiana University Bloomington (2004-2018) and Northeastern University (2018-present). Prof. Radivojac's research is in the areas of computational biology and machine learning with specific interests in protein function, genome interpretation, MS/MS proteomics, precision health, semi-supervised learning, and domain adaptation. He received the National Science Foundation (NSF) CAREER Award in 2007 and is a Fellow of the International Society for Computational Biology (ISCB). Prof. Radivojac was an August-Wilhelm Scheer Visiting Professor at Technical University of Munich (TUM) in 2016 as well as an honorary member of the Institute for Advanced Study at TUM in 2017. Prof. Radivojac's projects have been regularly supported by NSF and National Institutes of Health (NIH). He is currently an Editorial Board member for the journals Bioinformatics and Human Genetics, as well as the President of ISCB (2024-2027).