12-5949139-C-G

Position:

• chr12-5949139-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS2_Moderate PP4_Moderate PP3 PM2_Supporting PS4_Moderate PS3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.8318G>C variant in VWF is a missense variant predicted to cause substitution of cysteine by serine at amino acid 2773. This variant is absent from gnomAD v4.1 (PM2_Supporting). At least one patients with this variant displayed laboratory phenotypes of excessive mucocutaneous bleeding, very low VWF activity (measured by VWF:RCo assay), low VWF:RCo/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD Type 2A (PP4_moderate, PMID:17139364). This variant has been reported in 3 additional probands meeting type 2A laboratory criteria for PP4 (PS4_moderate; PMID:21979291, 32664776, 28971901), and one was a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID:32664776). Multimerization assay performed with the p.Cys2773Ser recombinant mutant and wild-type vWF co-expressed by HEK293 cells showed abnormal multimers (PMID:17139364 Fig. 2) that were counteracted by an allele-specific siRNA targeting the mutant transgene, indicating that this variant has a damaging effect on protein function (PMID:29734512)(PS3_supporting). The computational predictor REVEL gives a score of 0.876, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP4_Moderate, PS2_Moderate, PS4_Moderate, PS3, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228847/MONDO:0015628/081

• Frequency: Genomes: not found (cov: 33)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.70

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.8318G>C	p.Cys2773Ser	missense_variant	52/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.8318G>C	p.Cys2773Ser	missense_variant	52/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.8318G>C	p.Cys2773Ser	missense_variant	52/52	1	NM_000552.5	ENSP00000261405	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.70		Gain of disorder (P = 0.0014);
MVP		0.91
MPC		0.71
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.92
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61751311; hg19: chr12-6058305;