Table 1.
Data sets with experimental annotations
| Type of annotation | Database | Common SAVs (LDAF > 5%) | Rare SAVs (LDAV < 1%) |
|---|---|---|---|
| Protein–protein binding | |||
| Interface | PDB | 16 | 7710 |
| Other | PDB | 219 | 56,312 |
| Protein-DNA binding | |||
| Interface | PDB | 0 | 1182 |
| Other | PDB | 22 | 5706 |
| Protein-RNA binding | |||
| Interface | PDB | 2 | 420 |
| Other | PDB | 9 | 2488 |
| SUM ProNA binding | |||
| Interface | PDB | 18 | 9194 |
| Other | PDB | 247 | 62,983 |
| Effect | OMIM|HumVar|PMD | 149 | 7198 |
| SUM experimental | PDB| OMIM|HumVar|PMD | 404 | 78,993 |
| Variant (SAV) | ExAC | 34,309 | 6,639,624 |
Map of the 6,698,149 SAVs from the ExAC representing ~ 60 k individuals [5] onto high resolution (≤ 2.5 Å) structures from the PDB [3] to check how many SAVs are experimentally annotated at binding interfaces (labelled as interface in the 2nd column: closest residue atom within < 6 Å to substrate atom), with the three substrates being other proteins, DNA and RNA. PDB indicated usage of additional experimental data (Methods; all residues NOT explicitly annotated in a particular protein as binding were considered as “other”; in contrast to the ProNA2020 prediction method, this does not imply non-binding). The row labelled SUM ProNA binding summed over all annotations in each protein (due to possible double-binding, e.g. to DNA and RNA, the sum can be smaller than the parts). Overall 9212 SAVs (0.14%; 18 + 9194) had at least one positive ProNA-binding annotation in the PDB, and for another 63,230 SAVs (0.94%) there was some negative ProNA-binding annotation (the macro-molecule binding was in that experiment not found to bind at that position; note the total over all positive and negative ProNA-binding summed to 72,442 SAVs). The last row “Effect annotation” mapped variants from three databases annotating variant effects, namely OMIM [19], HumVar [20], and PMD [21] onto ExAC SAVs. For instance, 149 common SAVs and 7198 rare occurred at a residue position with an experimental effect (sum 0.11% of all SAVs). The total over both types of experimental annotations (binding/effect) provided the upper limit for SAVs with an experimental annotation about either binding or effect or both, namely 79,397 SAVs (1.2%): 404 of these for common SAVs and 78,993 for rare SAVs (2nd to last row labelled SUM experimental)