Severity scores were calculated for missense variants using web-based interfaces for PolyPhen2,13 SIFT,14 and GERP,15 using the default settings (Supplementary Information). PhyloP16 and Grantham Score17 were determined using an in-house annotated script. For nonsense/splice site variants the maximum score was assigned for Grantham, SIFT, and PolyPhen2; for GERP and PhyloP every possible coding base for the specific protein was scored and the highest value selected.
