rs11063987

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP5BA1

This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.4304A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 1435. TThe Grpmax filtering allele frequency in gnomAD v4.1 is 0.1104 (based on 8427/74964 alleles in the African American population[, including 498 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic 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 above the threshold of <0.6. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402552/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.032 ( 272 hom., cov: 31)

Exomes 𝑓: 0.0034 ( 238 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 1.84

Publications

10 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 -9 ACMG points.

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.4304A>G	p.Asn1435Ser	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4304A>G	p.Asn1435Ser	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.4304A>G	p.Asn1435Ser	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-25180A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0316

AC:

4809

AN:

152018

Hom.:

271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

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:

0.000662

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.00818

AC:

2054

AN:

251132

AF XY:

0.00611

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000485

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00343

AC:

5017

AN:

1461662

Hom.:

238

Cov.:

AF XY:

0.00294

AC XY:

2141

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.116

AC:

3890

AN:

33472

American (AMR)

AF:

0.00539

AC:

241

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000243

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000351

AC:

390

AN:

1111832

Other (OTH)

AF:

0.00732

AC:

442

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

351

701

1052

1402

1753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.0317

AC:

4817

AN:

152136

Hom.:

272

Cov.:

AF XY:

0.0308

AC XY:

2290

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.109

AC:

4537

AN:

41492

American (AMR)

AF:

0.0113

AC:

173

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000208

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68004

Other (OTH)

AF:

0.0265

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

208

417

625

834

1042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.00765

Hom.:

Bravo

AF:

0.0353

ESP6500AA

AF:

0.103

AC:

454

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00988

AC:

1199

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.4304A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 1435. TThe Grpmax filtering allele frequency in gnomAD v4.1 is 0.1104 (based on 8427/74964 alleles in the African American population[, including 498 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic 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 above the threshold of <0.6. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.4

PhyloP100

1.8

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.60

Sift

Benign

0.19

Sift4G

Benign

0.13

Polyphen

0.99

Vest4

0.15

MVP

0.91

MPC

0.62

ClinPred

0.013

GERP RS

4.3

Varity_R

0.14

gMVP

0.58

Mutation Taster

=89/11

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