We investigated the distribution of PTVs, variants predicted to disrupt protein-coding genes through the introduction of a stop codon or frameshift or the disruption of an essential splice site; such variants are expected to be enriched for complete loss of function of the impacted genes. Naturally-occurring PTVs in humans provide a model for the functional impact of gene inactivation, and have been used to identify many genes in which LoF causes severe disease30, as well as rare cases where LoF is protective against disease31.
