Fig. 7.

Protein features of missense variations on 3D structure provide intuitive insights into the effect of amino acid substitutions. (A) Structure (PDB ID code 2ING, chain: X) of BRCA1 with pathogenic (red) and population (blue) variations mapped, with an additional phenylalanine (Phe/F) at position 1704 (F1704) highlighted in pink for further analysis in this overview. (B) The 3D feature annotations for F1704. (C) Comparison of features of F1704 with protein class-specific 3D features associated to pathogenic and population variants (BRCA1 is annotated as a nucleic acid binding protein). A feature is highlighted in red if it matches a pathogenic variant-associated feature, or in blue if it matches a population variant-associated feature. In this example, F1704 possesses six pathogenic (${\mathrm{3}\mathrm{D}\mathrm{F}}^{\mathsf{P}\mathsf{A}\mathsf{T}\mathsf{H}}$) and zero population (${\mathrm{3}\mathrm{D}\mathrm{F}}^{\mathsf{P}\mathsf{O}\mathsf{P}}$) variant-associated 3D features. Thus, for F1704, P3DFi_{Nucleic acid binding} is equal to 6 – 0 = 6 (a positive P3DFi value represents a 3D mutational hotspot).