rs11063988

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP5BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.4138A>G variant in VWF is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1380. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1164 (based on 8878/74958 alleles in the African/African American population, including 541 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 VWD Type 2B patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic for VWD Type 2B by the ClinGen VWD Type 2 VCEP (BP5; PMID:30817071). At least 16 healthy adult individuals harboring the p.Asn1435Ser variant were found to be unaffected, with no diagnosis of a bleeding disorder and normal lab values, including bleeding scores lower than 4, VWF:RCo/VWF:Ag ratios >0.6, and no increased response to low-dose ristocetin (PMID:20231421). The mean VWF:RCo/VWF:Ag ratio of 0.71-0.77 within this group was significantly reduced compared to 0.91-0.97 for WT, but within the normal range. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. The computational predictor REVEL gives a score of 0.098, 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 is classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402595/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.034 ( 299 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 253 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.231

Publications

11 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.4138A>G	p.Ile1380Val	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4138A>G	p.Ile1380Val	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.4138A>G	p.Ile1380Val	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000538635.5 link	n.421-25346A>G		intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1 link	n.*248A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5093

AN:

151972

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.00850

AC:

2124

AN:

249900

AF XY:

0.00633

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00358

AC:

5231

AN:

1461654

Hom.:

253

Cov.:

AF XY:

0.00304

AC XY:

2208

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.121

AC:

4061

AN:

33470

American (AMR)

AF:

0.00588

AC:

263

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00556

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000359

AC:

399

AN:

1111840

Other (OTH)

AF:

0.00750

AC:

453

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

358

716

1075

1433

1791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0336

AC:

5103

AN:

152090

Hom.:

299

Cov.:

AF XY:

0.0326

AC XY:

2424

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.116

AC:

4817

AN:

41488

American (AMR)

AF:

0.0114

AC:

174

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.000208

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

67978

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

221

442

663

884

1105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0126

Hom.:

157

Bravo

AF:

0.0374

ESP6500AA

AF:

0.106

AC:

468

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0104

AC:

1260

EpiCase

AF:

0.000818

EpiControl

AF:

0.000952

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

May 06, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Nov 05, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000552.5:c.4138A>G variant in VWF is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1380. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1164 (based on 8878/74958 alleles in the African/African American population, including 541 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 VWD Type 2B patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic for VWD Type 2B by the ClinGen VWD Type 2 VCEP (BP5; PMID: 30817071). At least 16 healthy adult individuals harboring the p.Asn1435Ser variant were found to be unaffected, with no diagnosis of a bleeding disorder and normal lab values, including bleeding scores lower than 4, VWF:RCo/VWF:Ag ratios >0.6, and no increased response to low-dose ristocetin (PMID: 20231421). The mean VWF:RCo/VWF:Ag ratio of 0.71-0.77 within this group was significantly reduced compared to 0.91-0.97 for WT, but within the normal range. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. The computational predictor REVEL gives a score of 0.098, 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 is classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4, BP5. -

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

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.84

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.33

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

PhyloP100

0.23

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.020

REVEL

Benign

0.098

Sift

Benign

0.50

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.11

MPC

0.22

ClinPred

0.0031

GERP RS

-3.8

Varity_R

0.046

gMVP

0.46

Mutation Taster

=95/5

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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rs11063988

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