In silico prediction of novel variants in the CFD cohort
| Novel variants . | Protein . | Gene . | Exon/Intron . | Classification . | Fg:C/Fg:Ag (mg/dL) . | Bleeding severity . | In silico prediction . | |
|---|---|---|---|---|---|---|---|---|
| Scores . | Varsome . | |||||||
| c.1036G>C | p.Asp346His | FGG | Ex 8 | Hypodysfibrinogenemia | 45/117 | Grade 1 | CADD:28, SIFT:0, PolyPhen:1 | Likely pathogenic |
| c.425C>A | p.Ser142Ter | FGG | Ex 5 | Hypofibrinogenemia | 105/109 | Asymptomatic | CADD:36 | Likely pathogenic |
| c.115-610G>C | - | FGB | Int 1 | Afibrinogenemia | Undetectable | Grade 3 | varSEAK:1, CADD:6.9 | Not classified |
| Novel variants . | Protein . | Gene . | Exon/Intron . | Classification . | Fg:C/Fg:Ag (mg/dL) . | Bleeding severity . | In silico prediction . | |
|---|---|---|---|---|---|---|---|---|
| Scores . | Varsome . | |||||||
| c.1036G>C | p.Asp346His | FGG | Ex 8 | Hypodysfibrinogenemia | 45/117 | Grade 1 | CADD:28, SIFT:0, PolyPhen:1 | Likely pathogenic |
| c.425C>A | p.Ser142Ter | FGG | Ex 5 | Hypofibrinogenemia | 105/109 | Asymptomatic | CADD:36 | Likely pathogenic |
| c.115-610G>C | - | FGB | Int 1 | Afibrinogenemia | Undetectable | Grade 3 | varSEAK:1, CADD:6.9 | Not classified |
Four different in silico tools and VarSome were used to predict the effects of novel variants. These tools included Polymorphism Phenotypingv2 (PolyPhen-2), Sorting Intolerant from Tolerant (SIFT), and Combined Annotation Dependent Depletion (CADD). Splice variants were assessed using the varSEAK software and the CADD score. As we expected, nonsense variants were also predicted to be harmful using the CADD score.
Polyphen score: >0.908: probably damaging; >0.446 and ≤0.908: possibly damaging; ≤0.446: benign.
SIFT score: <0.05: deleterious; ≥0.05: tolerated.
CADD score: >20, deleterious
varSEAK classification: class 1, no splicing effect; class 2, likely no splicing effect; class 3, unknown splicing effect; class 4, likely splicing effect; and class 5, splicing effect.