chr12-6019448-C-T

Position:

chr12-6019448-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_ModeratePP3PP1PM2_SupportingPS3PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.3970G>A (p.Gly1324Ser) variant is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 1324. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and a decreased GP1b binding assay, which together are highly specific for VWD type 2M (PP4_moderate, PMID:30084138). The variant has been reported to segregate with VWD type 2M through 2 affected meioses from 1 family (PP1; PMID:29341351). At least 3 additional VWD type 2M probands have been reported with this variant (PMIDs: 29341351, 22102201, 1409710; PS4_moderate). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000003650 (based on 2/91074 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.718, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A platelet binding assay in COS-7 cells expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function. In a direct binding assay, the ristocetin-induced binding of rvWF(G1324S) to platelets was markedly reduced compared with rvWF(wt). (PMID:1409710) (PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP1, PP3, PP4_moderate, PS4_moderate. (VCEP specifications version Pilot; date of approval). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114147/MONDO:0015630/081

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

10

6

3

Clinical Significance

Pathogenic reviewed by expert panel P:4O:1

Conservation

PhyloP100: 4.73

Variant links:

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]

VWF links:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

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.

PP1

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 linkuse as main transcript	c.3970G>A	p.Gly1324Ser	missense_variant	28/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.3970G>A	p.Gly1324Ser	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.3970G>A	p.Gly1324Ser	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25514G>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152174

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

2

AN:

250604

Hom.:

0

AF XY:

0.00000737

AC XY:

1

AN XY:

135608

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

6

AN:

1461572

Hom.:

0

Cov.:

38

AF XY:

0.00000413

AC XY:

3

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152174

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

von Willebrand disease type 2M

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	Aug 13, 2024	The NM_000552.4(VWF):c.3970G>A (p.Gly1324Ser) variant is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 1324. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and a decreased GP1b binding assay, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 30084138). The variant has been reported to segregate with VWD type 2M through 2 affected meioses from 1 family (PP1; PMID: 29341351). At least 3 additional VWD type 2M probands have been reported with this variant (PMIDs: 29341351, 22102201, 1409710; PS4_moderate). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000003650 (based on 2/91074 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.718, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A platelet binding assay in COS-7 cells expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function. In a direct binding assay, the ristocetin-induced binding of rvWF(G1324S) to platelets was markedly reduced compared with rvWF(wt). (PMID: 1409710) (PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP1, PP3, PP4_moderate, PS4_moderate. (VCEP specifications version Pilot; date of approval). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2023	The frequency of this variant in the general population, 0.000008 (2/250604 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 2B and Type 2M VWD (PMIDs: 29341351 (2018), 27761512 (2016), 25185554 (2014), 22102201 (2011), and 1409710 (1992)). Functional studies demonstrated that this variant is damaging to protein function (PMIDs: 29341351 (2018), 27761512 (2016), 25185554 (2014), and 1409710 (1992)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

von Willebrand disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Apr 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.34

D

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

24

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Pathogenic

0.48

D

MetaRNN

Pathogenic

0.92

D

MetaSVM

Pathogenic

0.89

D

MutationAssessor

Pathogenic

3.7

H

PrimateAI

Uncertain

0.51

T

PROVEAN

Benign

-1.7

N

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0070

D

Sift4G

Uncertain

0.0030

D

Polyphen

1.0

D

Vest4

0.93

MutPred

0.68

Gain of catalytic residue at E1320 (P = 6e-04);

MVP

0.91

MPC

0.94

ClinPred

0.96

D

GERP RS

5.0

Varity_R

0.47

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61749398; hg19: chr12-6128614;