%0 Journal Article %A Antonio Rausell %A Pejman Mohammadi %A Paul J McLaren %A Ioannis Xenarios %A Jacques Fellay %A Amalio Telenti %T Analysis of stop-gain and frameshift variants in human innate immunity genes %D 2014 %R 10.1101/003376 %J bioRxiv %P 003376 %X Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to the innate immunity genes we first evaluated 17764 stop-gain and 13915 frameshift variants from the NHLBI Exome Sequencing Project and 1000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and non-sense mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against OMIM disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. %U https://www.biorxiv.org/content/biorxiv/early/2014/03/17/003376.full.pdf