Table 2.
Classification of Single Nucleotide Variants (SNVs) identified in this work.
| DNA change | Protein change | ACMG | Number of scores supporting pathogenicity | HSF | DVD | CSVS Allele Freq. | GnomAD Allele Freq. |
|---|---|---|---|---|---|---|---|
| c.160G > T | p.Glu54* |
Pathogenic (PVS1, PM2, PP1, PP3) |
6/9 | Activation of an exonic cryptic donor site. Potential alteration of splicing. Alteration of an exonic ESE site. Potential alteration of splicing. | N.A | 0 | 0 |
| c.781del | p.Thr261Argfs*34 |
Pathogenic (PVS1, PM2, PP1, PP3) |
N.A | Alteration of an exonic ESE site. Potential alteration of splicing. | N.A | 0 | 0 |
| c.1078C > A | p.Pro360Thr |
VUS (PM2, PP1, PP3, BP1) |
16/19 | No impact on splicing | VUS | 0 | 1.06e-5 (3 in 281904) |
| c.1107G > T | p.Glu369Asp |
Likely pathogenic (PS3, PM2, PP1, PP3, BP1) |
11/20 | Alteration of Wt donor site. Alteration of an exonic ESE site | N.A | 0 | 0 |
| c.1122G > T | p.Trp374Cys |
VUS (PM2, PP1, PP3, BP1) |
19/19 | Activation of an exonic cryptic donor site. | N.A | 0 | 0 |
| c.1281G > A | p.Glu427Glu |
Likely pathogenic (PS3, PM1, PM2, PP1, BP4) |
1/1 | Alteration of Wt donor site, most probably affecting splicing | N.A | 0 | 0 |
| c.1282-1G > A | — |
Pathogenic (PVS1, PS3, PM2, PP1, PP3) |
6/6 | Alteration of the Wt acceptor site, most probably affecting splicing. Activation of an intronic cryptic acceptor site. Potential alteration of splicing. | N.A | 0 | 0 |
| c.1601C > G | p.Ser534* |
Pathogenic (PVS1, PS3, PM1, PM2, PP1, PP3) |
7/9 | Creation of an exonic ESS site | N.A | 0 | 0 |
ACMG criteria: PVS1 (Pathogenic Very Strong): 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 of disease. PS3 (Pathogenic Strong 3): well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. PM1 (Pathogenic Moderate 1): located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM2 (Pathogenic Moderate 2): absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 (Pathogenic Supporting 1): cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PP3 (Pathogenic Supporting 3): multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). BP1 (Benign Supporting 1): missense variant in a gene for which primarily truncating variants are known to cause disease. BP4 (Benign Supporting 2): multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). All the databases were searched on the 22nd of March 2020.