The Exome Aggregation Consortium (ExAC) has computed a score called pLI, which indicates the probability that a gene is intolerant to a Loss of Function (LoF) mutation. This analysis is based on high-quality exome sequence data for 60,706 individuals of diverse ethnicities.

The ExAC consortium used a selection-neutral, sequence-context-based mutational model to compare the observed number of rare variants per gene to an expected number, then quantified deviation from expectation with a Z score (method described in Samocha et al.). To reduce confounding by coding sequence length, for Protein Truncating Variants (PTV) an expectation-maximization algorithm using the observed and expected PTV counts within each gene was used to separate genes into three categories:

The pLI score is the probability that a given gene falls into the Haploinsufficient category, therefore is extremely intolerant of loss-of-function variation. Genes with high pLI scores (pLI ≥ 0.9) are extremely LoF intolerant, whereby genes with low pLI scores (pLI ≤ 0.1) are LoF tolerant.

The manuscript describing this dataset and analysis (Lek et al.) is published in Nature.