Table 3.
ACMG classification of SRSF1 clinical variants before and after functional studies
| SRSF1 variant | Splicing deficient (Drosophila assay) | SRSF1 episignature | ACMG classification (before functional studies) | Total score | ACMG classification (after functional studies) | Total score |
|---|---|---|---|---|---|---|
| p.Ser126Trpfs∗17 | NA | Yes | Likely Pathogenic: PVS1, PM2 | 9 | Pathogenic: PVS1, PM2, PS3 | 13 |
| p.Val160Met | Yes | Yes | Likely Pathogenic: PP3, PM2, PP2, PS2 | 8 | Pathogenic: PP3, PM2, PP2, PS2, PS3 | 12 |
| p.Val194Serfs∗2 | Yes | Yes | Pathogenic: PVS1, PM2, PS2 | 13 | Pathogenic: PVS1, PM2, PS2, PS3 | 17 |
| p.Arg28∗ | NA | NA | Pathogenic: PVS1, PM2, PS2 | 13 | NA | NA |
| p.His183Arg | No | No | Likely Pathogenic: PM2, PP2, PS2 | 6 | Uncertain significance: PM2, PP2, PS2, BS3 | 2 |
| p.Gly40Val | Yes | NA | Likely Pathogenic: PP3, PM2, PP2, PS2 | 8 | Pathogenic: PP3, PM2, PP2, PS2, PS3 | 12 |
| p.Glu33∗ | NA | NA | Pathogenic: PVS1, PM2, PS2 | 13 | NA | NA |
| p.Ser201Valfs∗87 | Yes | Yes | Pathogenic: PVS1, PM2, PS2 | 13 | Pathogenic: PVS1, PM2, PS2, PS3 | 17 |
| p.Ala70Thr | Yes | NA | Likely Pathogenic: PP3, PM2, PP2, PS2 | 8 | Pathogenic: PP3, PM2, PP2, PS2, PS3 | 12 |
| p.Pro24Leu | Yes | NA | Likely Pathogenic: PP3, PM2, PP2, PS2 | 8 | Pathogenic: PP3, PM2, PP2, PS2, PS3 | 12 |
| p.Tyr77∗ | NA | Yes | Pathogenic: PVS1, PM2, PS2 | 13 | Pathogenic: PVS1, PM2, PS2, PS3 | 17 |
| p.Leu84Arg | Yes | Yes | Likely Pathogenic: PP3, PM2, PP2, PS2 | 8 | Pathogenic: PP3, PM2, PP2, PS2, PS3 | 12 |
| p.Asp44Asn | No | No | Uncertain significance: PM2, PP2, PS2, BP4 | 4 | Uncertain significance: PM2, PP2, PS2, BP4, BS3 | 0 |
ACMG variant classification using Varsome: PVS1 (very strong, +8 points): null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LoF is a known mechanism. PM2 (supporting, +1 point): absent from controls (or at extremely low frequency if recessive) (based on gnomAD frequencies). PP2 (supporting, +1 point): missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (based on gnomAD missense Z score). PP3 (moderate, +2 points): multiple lines of computational evidence support a deleterious effect on the gene or gene product (based on BayesDel_addAF score). PS2 (strong, +4 points): de novo (both maternity and paternity confirmed) in an individual with the disease and no family history. PS3 (strong, +4 points): well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. BS3 (strong, −4 points): well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. BP4 (moderate, −2 points): multiple lines of computational evidence suggest no impact on gene or gene product (based on BayesDel_addAF score).