We also explored the prevalence and functional impact of multinucleotide polymorphisms (MNPs), in cases where multiple substitutions were observed within the same codon in at least one individual. We found 5,945 MNPs (mean: 23 per sample) in ExAC (Extended Data Figure 2a) where analysis of the underlying SNPs without correct haplotype phasing would result in altered interpretation. These include 647 instances where the effect of a protein-truncating variant (PTV) variant is eliminated by an adjacent SNP (rescued PTV) and 131 instances where underlying synonymous or missense variants result in PTV MNPs (gained PTV). Additionally our analysis revealed 8 MNPs in disease-associated genes, resulting in either a rescued or gained PTV, and 10 MNPs that have previously been reported as disease causing mutations (Supplementary Information Table 10 and 11). We note that these variants would be missed by virtually all currently available variant calling and annotation pipelines.
