Disease: Von Willebrand Disease (VWD) Type 2A
Patient: 31 yo, Female
Variant1: VWF NC_000012.12: c.875-5T>Gdel, p.(Ser292_Glu333delinsLys) Causes complete exon 8 skipping
Variant2: VWF NM_000552.5: c.813C>G, p.(Tyr271*)
Phenotypes: History of bleeding (epistaxis, uncontrollable by conventional hemostatic treatment), Easy bruising, gum bleeding, excessive menstrual bleeding, mild decrease in plasma VWF:Ag, severe impairment in VWF function, VWF:Ab/VWF:Ag ratio decreased, VWF:CB/VWF:Ag ratio decreased, FVIII:C lvs slighly below normal range
Family: Son had bleeding diathesis and spontaneous epistaxis (less severe than proband), normal parents
In silico data available: SpliceAI delta score of 0.51 for loss of splice acceptor caused by variant 1
Alamut showed small to moderate effects of the variant on normal splicing of VWF
NetGene2 showed weak strength of 3' splice sites in exon 8
SpliceAid2 showed TIA-1 and TIAL 1, which bind to U-rich motifs and facilitate 5' splice site recognition where destroyed in the mutated sequence