Table 2 Overview of non-canonical splice-site variants in MYO15A
| Â | Variant | Predicted effect on pre-mRNA splicing | Number of patients | Â | In silico prediction | Minigene splicing assay | Zygosity | ACMG classification (Code) | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
CADD PHREAD | varSEAK Online | SpliceAI | MaxEntScan alt | MaxEntScan diff | MaxEntScan ret | |||||||
1 | c.3609+985G > A | Cryptic exon inclusion | 8 | 18.5 | Class 1: no splicing effect | Donor Loss: 0.27 | N/A | N/A | N/A | No | Het/ Hom | LP PS4+(PM2+PM3+PP1+PP3) |
2 | c.4142+5G > A | Exon Skipping | 2 | 25.7 | "Class 5: splicing effect (Loss of function for authentic Splice Site. Exon Skipping) | Donor Loss: 0.90 | 2.649 | 6.604 | 9.253 | No | Hom | VUS (PM2+PP3) |
3 | c.5134-10C > G | No splicing effect | 1 | 4.72 | Class 1: no splicing effect | 0 | 11.18 | 1.105 | 12.288 | No | Het | VUS (PM2+BP4) |
4 | c.5964+3G > A | Exon Skipping | 4 | 9.911 | Class 2: likely no splicing effect | Donor Gain:0.34 | 9.65 | -2.577 | 7.075 | No | Het | LP (PM2+PM3+PP1+PP3+PP5) |
5 | c.5965-8C > T | No splicing effect | 1 | 2.737 | Class 1: no splicing effect | Acceptor Gain:0.02 | 9.05 | 0.868 | 9.917 | No | Het | VUS (PM2+BP4) |
6 | c.6956+9C > G | Create ectopic splice site | 2 | 22.4 | "class 5: splicing effect (Use of a cryptic site 4 nt downstream of 3' ss | Donor Loss:0.66 | N/A | N/A | N/A | No | Het | VUS (PM2+PP3) |
7 | c.7395+3G > C | Create a cryptic splice donor site | 1 | 15.82 | Pos 6956+5: Strong increase of Score. New Splice Site.)" | Donor Loss:0.26 | 6.60 | 3.495 | 10.098 | No | Hom | VUS (PM2+PP3) |
8 | c.7395+3G > A | Exon skipping | 1 | 11.53 | "Class 5: splicing effect (Loss of function for authentic Splice Site. Exon Skipping | Acceptor Gain/Donor Gain:0.01 | 10.65 | -0.548 | 10.098 | No | Hom | VUS (PM2+PP3) |
9 | c.7787+4A > G | Exon skipping | 1 | 14.42 | "Class 4: likely splicing effect (Likely loss of function for authentic Splice Site. Exon Skipping | Donor Loss:0.15 | 6.32 | 0.841 | 7.162 | No | Hom | VUS (PM2+PP3) |
10 | c.8224+3A > G | Exon Skipping | 1 | 23.3 | Pos 7787 + 1: Decrease of Score for authentic Splice Site.)" | Donor Loss:0.79 | -4.99 | 5.665 | 0.674 | No | Hom | VUS (PM2+PP3) |
11 | c.8788+5G > T | Exon Skipping | 1 | 22.8 | "Class 4: likely splicing effect (Likely loss of function for authentic Splice Site. Exon Skipping | Donor Loss:0.82 | -3.85 | 7.146 | 3.292 | No | Hom | VUS (PM2+PP3) |
12 | c.9083+6 T > A | Exon Skipping | 1 | 23.9 | Pos 8224 + 1: Decrease of Score for authentic Splice Site.)" | Donor Loss:0.71 | 3.73 | 4.554 | 8.281 | Yes | Hom | LP (PS3+PM2+PP1+PP5+BP4) |