Performance of <i>in silico</i> predictors.

<p><b>(A)</b> A comparison between the observed enzymatic activity for each variant, sorted from lowest to highest %wt activity, to the binary predictions from PolyPhen and SIFT, on the third row. A red vertical line represents the division between missense mutations with ≤15% wt activity and those with >15% wt activity. <b>(B)</b> A Venn diagram showing the agreement between VUS observed to have ≤15% wt in our enzymatic activity assay and VUS categorized as “deleterious” by SIFT or “probably damaging” by PolyPhen. <b>(C)</b> Non-Finnish European incidence estimates obtained when considering only HGMD and LoF mutations (1 in 1,091,549), and when combining VUS with ≤15% wt activity (1 in 355,502), VUS categorized as “deleterious” by SIFT (1 in 255,344), VUS categorized as “probably damaging” by PolyPhen (1 in 288,327), or variants categorized as “deleterious” by SIFT and “probably damaging” by PolyPhen (1 in 438,641) with HGMD+LoF variants. VUS with an allele frequency in ExAC greater than 0.1% or for which one or more homozygous individuals were observed were excluded from estimates using SIFT and PolyPhen.