rs1800384

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000552.5(VWF):c.4665A>C(p.Ala1555Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,612,132 control chromosomes in the GnomAD database, including 14,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.095 ( 1316 hom., cov: 31)

Exomes 𝑓: 0.11 ( 12934 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: -0.722

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 12-6018753-T-G is Benign according to our data. Variant chr12-6018753-T-G is described in ClinVar as Benign. ClinVar VariationId is 256681.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=-0.722 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.4665A>C	p.Ala1555Ala	synonymous_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4665A>C	p.Ala1555Ala	synonymous_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.4665A>C	p.Ala1555Ala	synonymous_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-24819A>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0946

AC:

14386

AN:

152022

Hom.:

1306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.373

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.0372

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0852

Gnomad OTH

AF:

0.102

GnomAD2 exomes

AF:

0.153

AC:

38173

AN:

249792

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.370

Gnomad ASJ exome

AF:

0.0782

Gnomad EAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.0418

Gnomad NFE exome

AF:

0.0837

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.107

AC:

155958

AN:

1459992

Hom.:

12934

Cov.:

AF XY:

0.109

AC XY:

78873

AN XY:

726198

show subpopulations

African (AFR)

AF:

0.0177

AC:

594

AN:

33468

American (AMR)

AF:

0.353

AC:

15717

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.0767

AC:

2002

AN:

26118

East Asian (EAS)

AF:

0.397

AC:

15713

AN:

39618

South Asian (SAS)

AF:

0.200

AC:

17264

AN:

86138

European-Finnish (FIN)

AF:

0.0446

AC:

2368

AN:

53054

Middle Eastern (MID)

AF:

0.0981

AC:

557

AN:

5678

European-Non Finnish (NFE)

AF:

0.0854

AC:

94915

AN:

1111098

Other (OTH)

AF:

0.113

AC:

6828

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

7041

14082

21124

28165

35206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3874

7748

11622

15496

19370

<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:

0.0947

AC:

14412

AN:

152140

Hom.:

1316

Cov.:

AF XY:

0.100

AC XY:

7473

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0232

AC:

962

AN:

41524

American (AMR)

AF:

0.246

AC:

3763

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

259

AN:

3472

East Asian (EAS)

AF:

0.374

AC:

1921

AN:

5132

South Asian (SAS)

AF:

0.218

AC:

1051

AN:

4820

European-Finnish (FIN)

AF:

0.0372

AC:

395

AN:

10608

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0852

AC:

5794

AN:

67986

Other (OTH)

AF:

0.105

AC:

222

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

610

1220

1829

2439

3049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.0864

Hom.:

208

Bravo

AF:

0.108

Asia WGS

AF:

0.290

AC:

1007

AN:

3478

EpiCase

AF:

0.0794

EpiControl

AF:

0.0831

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

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

Nov 05, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000552.5(VWF):c.4665A>C, p.Ala1555= variant in VWF is a synonymous variant. TheGrpmax filtering allele frequency in gnomAD v4.1 is 0.3892 (based on 17634/44750 alleles, with 3489 homozygotes in the East Asian population), which is above the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor SpliceAI gives a score of 0.0, which meets criteria for BP7. This variant is classified as benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP7 -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

(source)

DANN

Benign

0.39

PhyloP100

-0.72

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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