Figure 7.
Analyses of the variants in the 6 FVIII domains. (A) The number of missense variants in each of the 6 FVIII domains is shown above the green bars. If the number of the 2863 missense variants is normalized in proportion to the amino acid residues present in each domain, the outcome is shown as orange bars. The missense variants in the linker regions and the signal peptide are not shown. (B) The 7 distribution types of the 1281 variants in the B domain (pink) are compared against those for all 6211 genetic variants that occur across all the protein domains in FVIII (blue). (C) The PolyPhen-2 substitution analyses predict the damaging effects of all 2863 variants from across the entire protein structure, based on the AlphaFold-predicted FVIII structure. (D) The SIFT substitution analyses predict the damaging effects of 2863 variants from across the entire protein structure based on the AlphaFold-predicted FVIII structure. (E) The FATHMM substitution analyses predict the damaging effects of 2584 missense variants from across the entire protein structure based on the AlphaFold-predicted FVIII structure. This excludes synonymous variants that are not considered by this software. (F) Accessibility analyses of 2863 missense variants in the FVIIIa crystal structure (PDB ID 6MF2). The FVIII variants were grouped by their phenotypic classification (severity) and subdivided according to the residue surface accessibility (ACC) determined using DSSP (see “Methods”). Accessibilities of 0 to 1 indicate full side chain burial; values of 2 to 3 indicate increased side-chain exposure to solvent; and values of ≥4 indicate high solvent exposure. The ACC values for the B domain (Figure 3) all indicated full surface exposures, in keeping with its predicted disordered structure.

Analyses of the variants in the 6 FVIII domains. (A) The number of missense variants in each of the 6 FVIII domains is shown above the green bars. If the number of the 2863 missense variants is normalized in proportion to the amino acid residues present in each domain, the outcome is shown as orange bars. The missense variants in the linker regions and the signal peptide are not shown. (B) The 7 distribution types of the 1281 variants in the B domain (pink) are compared against those for all 6211 genetic variants that occur across all the protein domains in FVIII (blue). (C) The PolyPhen-2 substitution analyses predict the damaging effects of all 2863 variants from across the entire protein structure, based on the AlphaFold-predicted FVIII structure. (D) The SIFT substitution analyses predict the damaging effects of 2863 variants from across the entire protein structure based on the AlphaFold-predicted FVIII structure. (E) The FATHMM substitution analyses predict the damaging effects of 2584 missense variants from across the entire protein structure based on the AlphaFold-predicted FVIII structure. This excludes synonymous variants that are not considered by this software. (F) Accessibility analyses of 2863 missense variants in the FVIIIa crystal structure (PDB ID 6MF2). The FVIII variants were grouped by their phenotypic classification (severity) and subdivided according to the residue surface accessibility (ACC) determined using DSSP (see “Methods”). Accessibilities of 0 to 1 indicate full side chain burial; values of 2 to 3 indicate increased side-chain exposure to solvent; and values of ≥4 indicate high solvent exposure. The ACC values for the B domain (Figure 3) all indicated full surface exposures, in keeping with its predicted disordered structure.

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