chr12-6064267-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.1411G>A(p.Val471Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,614,044 control chromosomes in the GnomAD database, including 11,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1091 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10753 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.00400

Publications

26 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 -19 ACMG points.

PP2

Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease 1, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease type 2M, von Willebrand disease 3, von Willebrand disease type 2N.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015455186).

BP6

Variant 12-6064267-C-T is Benign according to our data. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.1411G>A	p.Val471Ile	missense_variant	Exon 12 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.1411G>A	p.Val471Ile	missense_variant	Exon 12 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.1411G>A	p.Val471Ile	missense_variant	Exon 12 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.420+46248G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17587

AN:

152142

Hom.:

1092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0625

Gnomad ASJ

AF:

0.0424

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.0930

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.0918

GnomAD2 exomes

AF:

0.114

AC:

28579

AN:

250654

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.0483

Gnomad ASJ exome

AF:

0.0507

Gnomad EAS exome

AF:

0.171

Gnomad FIN exome

AF:

0.0983

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.117

AC:

171222

AN:

1461782

Hom.:

10753

Cov.:

AF XY:

0.119

AC XY:

86576

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.132

AC:

4431

AN:

33480

American (AMR)

AF:

0.0501

AC:

2242

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0490

AC:

1281

AN:

26134

East Asian (EAS)

AF:

0.163

AC:

6463

AN:

39698

South Asian (SAS)

AF:

0.175

AC:

15062

AN:

86256

European-Finnish (FIN)

AF:

0.0995

AC:

5306

AN:

53352

Middle Eastern (MID)

AF:

0.0970

AC:

559

AN:

5762

European-Non Finnish (NFE)

AF:

0.116

AC:

128862

AN:

1111980

Other (OTH)

AF:

0.116

AC:

7016

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9872

19743

29615

39486

49358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4736

9472

14208

18944

23680

<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:

0.116

AC:

17590

AN:

152262

Hom.:

1091

Cov.:

AF XY:

0.114

AC XY:

8474

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.139

AC:

5758

AN:

41550

American (AMR)

AF:

0.0623

AC:

953

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

147

AN:

3468

East Asian (EAS)

AF:

0.169

AC:

873

AN:

5168

South Asian (SAS)

AF:

0.176

AC:

849

AN:

4820

European-Finnish (FIN)

AF:

0.0930

AC:

987

AN:

10610

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7754

AN:

68018

Other (OTH)

AF:

0.0908

AC:

192

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

819

1638

2458

3277

4096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.114

Hom.:

3360

Bravo

AF:

0.112

TwinsUK

AF:

0.115

AC:

427

ALSPAC

AF:

0.111

AC:

428

ESP6500AA

AF:

0.139

AC:

611

ESP6500EA

AF:

0.110

AC:

948

ExAC

AF:

0.118

AC:

14348

Asia WGS

AF:

0.166

AC:

576

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 11, 2020

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

- -

Oct 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: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

- -

Hereditary von Willebrand disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.2

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.25

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.055

PhyloP100

0.0040

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.37

REVEL

Benign

0.13

Sift

Benign

0.96

Sift4G

Benign

1.0

Polyphen

0.019

Vest4

0.038

MPC

0.21

ClinPred

0.0031

GERP RS

-2.9

Varity_R

0.032

gMVP

0.12

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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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