rs34510401

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_ModerateBP6_Very_StrongBP7BS1BS2_Supporting

The NM_000552.5(VWF):c.2586G>T(p.Val862Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,248 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene VWF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0012 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 15 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0410

Publications

1 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 12-6034787-C-A is Benign according to our data. Variant chr12-6034787-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 439329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.041 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00133 (1940/1461890) while in subpopulation MID AF = 0.00728 (42/5768). AF 95% confidence interval is 0.0061. There are 15 homozygotes in GnomAdExome4. There are 1176 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2586G>T	p.Val862Val	synonymous	Exon 20 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.2586G>T	p.Val862Val	synonymous	Exon 20 of 52	ENSP00000261405.5	P04275-1
VWF	ENST00000895679.1		c.2586G>T	p.Val862Val	synonymous	Exon 21 of 53	ENSP00000565738.1
VWF	ENST00000895680.1		c.2586G>T	p.Val862Val	synonymous	Exon 20 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000896

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00236

AC:

594

AN:

251486

AF XY:

0.00286

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00133

AC:

1940

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1176

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00165

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

504

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00655

AC:

565

AN:

86258

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000513

AC:

571

AN:

1112012

Other (OTH)

AF:

0.00248

AC:

150

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

123

245

368

490

613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00125

AC:

190

AN:

152358

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41586

American (AMR)

AF:

0.00137

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68038

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00219

Hom.:

Bravo

AF:

0.00101

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

VWF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

1.5

(source)

DANN

Benign

0.68

PhyloP100

0.041

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over