12-6057995-T-C

Position:

• chr12-6057995-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3 PP4_Moderate PP1 PM2_Supporting PS3

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.1583A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 528. This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant has been reported homozygous in two homozygous (PM3) probands meeting the VWD type 2A phenotypic criteria (PP4_moderate, PS4_suporting; PMID:20335223; 9714529). The variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID:20335223). There is evidence of defective VWF storage with no response to desmopressin and very little VWF:Ag released after administration. Expression in 293 EBNA cells showed that homozygous N528S-VWF secretion was 7.5% of WT, with a multimer pattern lacking medium and HMWMs (PMID:20335223 Fig. 4; PS3). Expression in AtT-20 cells showed that the N528S-VWF is not multimerized and is not trafficked to storage granules. 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: PM2_supporting, PP4_moderate, PM3, PP1, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114178/MONDO:0015628/081

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 7.46

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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1583A>G	p.Asn528Ser	missense_variant	14/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1583A>G	p.Asn528Ser	missense_variant	14/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1583A>G	p.Asn528Ser	missense_variant	14/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.420+52520A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250246 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

von Willebrand disease type 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Apr 26, 2022

- -

Von Willebrand disease type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 03, 2010

- -

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.63		Gain of catalytic residue at N528 (P = 0);
MVP		0.89
MPC		0.65
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.79
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs61754010; hg19: chr12-6167161;