12-6018919-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP2BP4_Strong

The NM_000552.5(VWF):c.4499C>T(p.Ala1500Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1500E) has been classified as Uncertain significance. The gene VWF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.02

Publications

6 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 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
von Willebrand disease type 2B
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
von Willebrand disease 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 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, 11 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 von Willebrand disease type 2N, von Willebrand disease type 2B, von Willebrand disease type 2M, von Willebrand disease 2, hereditary von Willebrand disease, von Willebrand disease type 2A, von Willebrand disease 1, von Willebrand disease 3.

BP4

Computational evidence support a benign effect (MetaRNN=0.01448074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.4499C>T	p.Ala1500Val	missense	Exon 28 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWF	ENST00000261405.10	TSL:1 MANE Select	c.4499C>T	p.Ala1500Val	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
VWF	ENST00000895679.1		c.4499C>T	p.Ala1500Val	missense	Exon 29 of 53	ENSP00000565738.1
VWF	ENST00000895680.1		c.2967+10423C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000259

AC:

AN:

250966

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00123

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111840

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000985

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00232

AC:

AN:

5166

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000189

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

9.6

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.33

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.6

PhyloP100

2.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.060

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.12

Vest4

0.17

MutPred

0.51

Gain of catalytic residue at E1504 (P = 5e-04)

MVP

0.40

MPC

0.27

ClinPred

0.011

GERP RS

1.3

Varity_R

0.15

gMVP

0.47

Mutation Taster

=30/70

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over