chr12-6034818-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBA1

The NM_000552.5(VWF):c.2555A>G(p.Gln852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 1,614,050 control chromosomes in the GnomAD database, including 662,737 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q852E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.92 ( 64098 hom., cov: 33)

Exomes 𝑓: 0.90 ( 598639 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.552

Publications

59 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.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000552.5

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=5.94502E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 20 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 20 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 20 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-40884A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.917

AC:

139460

AN:

152158

Hom.:

64045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.951

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.922

Gnomad ASJ

AF:

0.941

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.876

Gnomad FIN

AF:

0.897

Gnomad MID

AF:

0.917

Gnomad NFE

AF:

0.908

Gnomad OTH

AF:

0.924

GnomAD2 exomes

AF:

0.900

AC:

226185

AN:

251332

AF XY:

0.898

show subpopulations

Gnomad AFR exome

AF:

0.951

Gnomad AMR exome

AF:

0.917

Gnomad ASJ exome

AF:

0.945

Gnomad EAS exome

AF:

0.794

Gnomad FIN exome

AF:

0.895

Gnomad NFE exome

AF:

0.908

Gnomad OTH exome

AF:

0.909

GnomAD4 exome

AF:

0.905

AC:

1322288

AN:

1461774

Hom.:

598639

Cov.:

AF XY:

0.903

AC XY:

656815

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.954

AC:

31945

AN:

33476

American (AMR)

AF:

0.916

AC:

40966

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.945

AC:

24700

AN:

26136

East Asian (EAS)

AF:

0.795

AC:

31553

AN:

39694

South Asian (SAS)

AF:

0.869

AC:

74934

AN:

86248

European-Finnish (FIN)

AF:

0.888

AC:

47455

AN:

53418

Middle Eastern (MID)

AF:

0.922

AC:

5318

AN:

5768

European-Non Finnish (NFE)

AF:

0.909

AC:

1010614

AN:

1111926

Other (OTH)

AF:

0.908

AC:

54803

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

7213

14427

21640

28854

36067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21484

42968

64452

85936

107420

<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:

0.917

AC:

139570

AN:

152276

Hom.:

64098

Cov.:

AF XY:

0.915

AC XY:

68148

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.951

AC:

39517

AN:

41558

American (AMR)

AF:

0.922

AC:

14110

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.941

AC:

3266

AN:

3472

East Asian (EAS)

AF:

0.792

AC:

4098

AN:

5174

South Asian (SAS)

AF:

0.877

AC:

4226

AN:

4818

European-Finnish (FIN)

AF:

0.897

AC:

9518

AN:

10610

Middle Eastern (MID)

AF:

0.921

AC:

269

AN:

292

European-Non Finnish (NFE)

AF:

0.908

AC:

61784

AN:

68022

Other (OTH)

AF:

0.919

AC:

1940

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

593

1186

1778

2371

2964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.910

Hom.:

289495

Bravo

AF:

0.921

ESP6500AA

AF:

0.950

AC:

4184

ESP6500EA

AF:

0.911

AC:

7832

ExAC

AF:

0.899

AC:

109150

Asia WGS

AF:

0.840

AC:

2924

AN:

3478

EpiCase

AF:

0.914

EpiControl

AF:

0.918

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.9

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.30

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.010

MetaRNN

Benign

5.9e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.42

PhyloP100

-0.55

PrimateAI

Benign

0.25

PROVEAN

Benign

1.3

REVEL

Benign

0.086

Sift

Benign

1.0

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.037

MPC

0.20

ClinPred

0.00065

GERP RS

0.42

Varity_R

0.045

gMVP

0.38

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over