NM_000552.5:c.1728G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.1728G>T is a missense variant in VWF that replaces methionine with isoleucine at position 576. The The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02820 (based on 1745/59454 alleles in the Admixed American population, with 41 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in the heterozygous state in at least 6 patients with a diagnosed blood disorder, with several exhibiting mild or moderate reduction of VWF:Ag (PMID:17190853, PMID:25780857, PMID:33556167). However, diagnoses are not consistent and the variant is ineligible for consideration for PS4 due to its high frequency in the control population. The computational predictor REVEL gives a score of 0.038, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228284/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 38 hom. )

Consequence

VWF
NM_000552.5 missense, splice_region

Scores

Splicing: ADA: 0.03487

Clinical Significance

Likely benign reviewed by expert panel U:1B:6O:1

Conservation

PhyloP100: 1.52

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

hereditary von Willebrand disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
von Willebrand disease type 2B
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
von Willebrand disease 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
von Willebrand disease 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
von Willebrand disease type 2A
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease type 2M
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease type 2N
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VWF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.1728G>T	p.Met576Ile	missense_variant, splice_region_variant	Exon 14 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.1728G>T	p.Met576Ile	missense_variant, splice_region_variant	Exon 14 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.1728G>T	p.Met576Ile	missense_variant, splice_region_variant	Exon 14 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.420+52665G>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00546

AC:

1332

AN:

243966

AF XY:

0.00410

show subpopulations

Gnomad AFR exome

AF:

0.000191

Gnomad AMR exome

AF:

0.0377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.00434

GnomAD4 exome

AF:

0.00117

AC:

1707

AN:

1454016

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

731

AN XY:

722530

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33280

American (AMR)

AF:

0.0349

AC:

1540

AN:

44144

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25706

East Asian (EAS)

AF:

0.000126

AC:

AN:

39606

South Asian (SAS)

AF:

0.000223

AC:

AN:

85368

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52266

Middle Eastern (MID)

AF:

0.000368

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.0000830

AC:

AN:

1108136

Other (OTH)

AF:

0.000699

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00160

AC:

243

AN:

152320

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41572

American (AMR)

AF:

0.0134

AC:

205

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000696

Hom.:

Bravo

AF:

0.00307

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00443

AC:

537

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3Other:1

Aug 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Academic Unit of Haematology, University of Sheffield

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 24, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 07, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Sep 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, PM1 -

Hereditary von Willebrand disease

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000552.5:c.1728G>T is a missense variant in VWF that replaces methionine with isoleucine at position 576. The The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02820 (based on 1745/59454 alleles in the Admixed American population, with 41 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in the heterozygous state in at least 6 patients with a diagnosed blood disorder, with several exhibiting mild or moderate reduction of VWF:Ag (PMID: 17190853, PMID: 25780857, PMID: 33556167). However, diagnoses are not consistent and the variant is ineligible for consideration for PS4 due to its high frequency in the control population. The computational predictor REVEL gives a score of 0.038, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. -

not specified

Benign:1

Feb 05, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.38

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

REVEL

Benign

0.038

Sift

Benign

0.065

Sift4G

Benign

0.28

Polyphen

0.0060

Vest4

0.14

MutPred

0.37

Gain of catalytic residue at N573 (P = 0.0015);

MVP

0.44

MPC

0.21

ClinPred

0.016

GERP RS

1.4

Varity_R

0.20

gMVP

0.42

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.035

dbscSNV1_RF

Benign

0.076

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over