rs2270152

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.8116-20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,612,966 control chromosomes in the GnomAD database, including 35,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point.. The gene VWF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.17 ( 2428 hom., cov: 32)

Exomes 𝑓: 0.21 ( 32613 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.45

Publications

14 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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 12-5951903-T-G is Benign according to our data. Variant chr12-5951903-T-G is described in ClinVar as Benign. ClinVar VariationId is 256703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

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.8116-20A>C		intron	N/A	NP_000543.3	P04275-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VWF	ENST00000261405.10	TSL:1 MANE Select	c.8116-20A>C	intron	N/A	ENSP00000261405.5	P04275-1
VWF	ENST00000895679.1		c.8116-20A>C	intron	N/A	ENSP00000565738.1
VWF	ENST00000895680.1		c.3196-20A>C	intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

25972

AN:

152010

Hom.:

2431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0922

Gnomad AMI

AF:

0.256

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.194

AC:

48786

AN:

251342

AF XY:

0.201

show subpopulations

Gnomad AFR exome

AF:

0.0918

Gnomad AMR exome

AF:

0.149

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.212

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.208

AC:

304456

AN:

1460838

Hom.:

32613

Cov.:

AF XY:

0.210

AC XY:

152314

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.0894

AC:

2992

AN:

33474

American (AMR)

AF:

0.147

AC:

6584

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

6244

AN:

26126

East Asian (EAS)

AF:

0.171

AC:

6784

AN:

39694

South Asian (SAS)

AF:

0.230

AC:

19830

AN:

86230

European-Finnish (FIN)

AF:

0.176

AC:

9417

AN:

53404

Middle Eastern (MID)

AF:

0.220

AC:

1270

AN:

5766

European-Non Finnish (NFE)

AF:

0.215

AC:

238355

AN:

1111054

Other (OTH)

AF:

0.215

AC:

12980

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

11810

23620

35429

47239

59049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8268

16536

24804

33072

41340

<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:

0.171

AC:

25981

AN:

152128

Hom.:

2428

Cov.:

AF XY:

0.169

AC XY:

12578

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0924

AC:

3835

AN:

41500

American (AMR)

AF:

0.159

AC:

2438

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

855

AN:

3464

East Asian (EAS)

AF:

0.180

AC:

929

AN:

5162

South Asian (SAS)

AF:

0.219

AC:

1053

AN:

4816

European-Finnish (FIN)

AF:

0.172

AC:

1826

AN:

10598

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14350

AN:

67982

Other (OTH)

AF:

0.188

AC:

397

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1091

2181

3272

4362

5453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.194

Hom.:

729

Bravo

AF:

0.169

Asia WGS

AF:

0.213

AC:

740

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.056

(source)

DANN

Benign

0.26

PhyloP100

-4.5

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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