chr12-6019277-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP5BP4BA1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000552.5(VWF):c.4141A>G (p.Thr1381Ala) is common in the general population with a Grpmax filtering allele frequency of 0.8925 (based on 67313/74942 alleles in the African/African American population) in gnomAD v4.1 (BA1). Several probands have been reported (PMID:30817071, PMID:30762591) with Thr1381Ala in cis or trans with additional vWF variants, including the type 2B Arg1308Cys variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP; BP5). and therefore meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4, BP5 (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; 08/12/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402593/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.72 ( 39998 hom., cov: 30)

Exomes 𝑓: 0.64 ( 301018 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11

Conservation

PhyloP100: 1.88

Publications

53 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: Benign. The variant received -10 ACMG points.

BP4

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

BP5

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

BA1

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.4141A>G	p.Thr1381Ala	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4141A>G	p.Thr1381Ala	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.4141A>G	p.Thr1381Ala	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-25343A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.715

AC:

108580

AN:

151844

Hom.:

39958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.893

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.753

Gnomad ASJ

AF:

0.684

Gnomad EAS

AF:

0.747

Gnomad SAS

AF:

0.765

Gnomad FIN

AF:

0.549

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.619

Gnomad OTH

AF:

0.724

GnomAD2 exomes

AF:

0.686

AC:

170206

AN:

248236

AF XY:

0.681

show subpopulations

Gnomad AFR exome

AF:

0.897

Gnomad AMR exome

AF:

0.806

Gnomad ASJ exome

AF:

0.680

Gnomad EAS exome

AF:

0.762

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.616

Gnomad OTH exome

AF:

0.678

GnomAD4 exome

AF:

0.638

AC:

931862

AN:

1461560

Hom.:

301018

Cov.:

AF XY:

0.640

AC XY:

465156

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.905

AC:

30285

AN:

33472

American (AMR)

AF:

0.802

AC:

35882

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

17889

AN:

26132

East Asian (EAS)

AF:

0.738

AC:

29289

AN:

39700

South Asian (SAS)

AF:

0.743

AC:

64124

AN:

86250

European-Finnish (FIN)

AF:

0.551

AC:

29395

AN:

53390

Middle Eastern (MID)

AF:

0.765

AC:

4410

AN:

5762

European-Non Finnish (NFE)

AF:

0.612

AC:

680452

AN:

1111764

Other (OTH)

AF:

0.665

AC:

40136

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

20564

41128

61691

82255

102819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18492

36984

55476

73968

92460

<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:

0.715

AC:

108674

AN:

151962

Hom.:

39998

Cov.:

AF XY:

0.717

AC XY:

53254

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.893

AC:

37028

AN:

41470

American (AMR)

AF:

0.754

AC:

11512

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.684

AC:

2373

AN:

3468

East Asian (EAS)

AF:

0.747

AC:

3841

AN:

5142

South Asian (SAS)

AF:

0.766

AC:

3680

AN:

4806

European-Finnish (FIN)

AF:

0.549

AC:

5788

AN:

10536

Middle Eastern (MID)

AF:

0.786

AC:

231

AN:

294

European-Non Finnish (NFE)

AF:

0.619

AC:

42073

AN:

67946

Other (OTH)

AF:

0.720

AC:

1520

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1474

2948

4423

5897

7371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.658

Hom.:

27088

Bravo

AF:

0.739

TwinsUK

AF:

0.612

AC:

2269

ALSPAC

AF:

0.617

AC:

2377

ESP6500AA

AF:

0.882

AC:

3886

ESP6500EA

AF:

0.620

AC:

5331

ExAC

AF:

0.680

AC:

82506

Asia WGS

AF:

0.772

AC:

2686

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Feb 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Allele frequency is common in at least one population database (frequency: 89.735% in gnomAD_Exomes) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary von Willebrand disease

Benign:2

Aug 13, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The missense variant NM_000552.5(VWF):c.4141A>G (p.Thr1381Ala) is common in the general population with a Grpmax filtering allele frequency of 0.8925 (based on 67313/74942 alleles in the African/African American population) in gnomAD v4.1 (BA1). Several probands have been reported (PMID: 30817071, PMID: 30762591) with Thr1381Ala in cis or trans with additional vWF variants, including the type 2B Arg1308Cys variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP; BP5). and therefore meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4, BP5 (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; 08/12/2024). -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

von Willebrand disease type 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

von Willebrand disease type 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

von Willebrand disease type 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

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

0.070

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.14

(source)

DANN

Benign

0.18

DEOGEN2

Benign

0.33

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0000053

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.1

PhyloP100

1.9

PrimateAI

Benign

0.27

PROVEAN

Benign

1.1

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.045

MPC

0.26

ClinPred

0.0086

GERP RS

0.20

Varity_R

0.11

gMVP

0.56

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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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