Fig. 1: Study design and characterization of coding variation in F12.

a Moderately rare (MAF ≤ 1%) variant filtering strategy, and b distribution and frequencies of high confidence loss-of-function (FIS = 1.0, MAF ≤ 1%) coding variants in the F12 locus identified in the UK Biobank (UKB) and NIH All of Us (AoU) datasets. There were 31 unique essential splice site variants that fell outside the exon boundaries and are not shown. Amino acids 1-19 (gray) comprise the FXII signal peptide. c Study breakdown by biobank and subpopulation as determined by principal components analysis of genetic ancestry. d For each moderately rare F12 variant, the in-cohort MAF was computed and plotted against the FIS value. All missense and HCLOF variants with in-cohort MAF ≤ 1% were included across the full range of FIS assignments.  Variants are shown stratified by the dataset in which they were found (“UKB” or “AoU”), with variants shared across both datasets noted (“Both”). e Variant counts for F12 are shown according to FIS threshold (black circles). For comparison, the in-group median variant allele count (MAF ≤ 1%) at each FIS threshold is shown for two gene sets: vitamin K (VK)-dependent coagulation factors (F2, F7, F9, F10) (orange squares) and the larger group of essential humoral coagulation factors (F2, F5, F7, F8, F9, F10) (red triangles). Variant counts for F12 and each gene set were normalized to the number of variants at the FIS = 0 threshold. Abbreviations: FIS functional impact score, FN2 fibronectin type 2 domain, EGF EGF-like domain, FN1 fibronectin type 1 domain, KD kringle domain, PRR proline rich region, AFR African, AMR admixed American, EAS East Asian, EUR European, SAS South Asian, MID Middle Eastern, MAF minor allele frequency, VK vitamin K-dependent.