rs216902

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5844C>T(p.Cys1948Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,607,762 control chromosomes in the GnomAD database, including 133,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11845 hom., cov: 32)

Exomes 𝑓: 0.40 ( 121815 hom. )

Consequence

VWF
NM_000552.5 splice_region, synonymous

Scores

Splicing: ADA: 0.00001009

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.04

Publications

24 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=-0.48).

BP6

Variant 12-5996221-G-A is Benign according to our data. Variant chr12-5996221-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.5844C>T	p.Cys1948Cys	splice_region_variant, synonymous_variant	Exon 35 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.5844C>T	p.Cys1948Cys	splice_region_variant, synonymous_variant	Exon 35 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.5844C>T	p.Cys1948Cys	splice_region_variant, synonymous_variant	Exon 35 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5 link	n.421-2287C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58298

AN:

151844

Hom.:

11821

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.413

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.744

Gnomad SAS

AF:

0.525

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.377

Gnomad OTH

AF:

0.378

GnomAD2 exomes

AF:

0.438

AC:

106712

AN:

243910

AF XY:

0.438

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.528

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.743

Gnomad FIN exome

AF:

0.395

Gnomad NFE exome

AF:

0.374

Gnomad OTH exome

AF:

0.397

GnomAD4 exome

AF:

0.401

AC:

583244

AN:

1455798

Hom.:

121815

Cov.:

AF XY:

0.404

AC XY:

292222

AN XY:

723872

show subpopulations

African (AFR)

AF:

0.307

AC:

10233

AN:

33372

American (AMR)

AF:

0.515

AC:

22659

AN:

43972

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

8566

AN:

26030

East Asian (EAS)

AF:

0.783

AC:

31005

AN:

39600

South Asian (SAS)

AF:

0.524

AC:

44839

AN:

85498

European-Finnish (FIN)

AF:

0.401

AC:

21297

AN:

53128

Middle Eastern (MID)

AF:

0.328

AC:

1747

AN:

5328

European-Non Finnish (NFE)

AF:

0.378

AC:

418696

AN:

1108726

Other (OTH)

AF:

0.402

AC:

24202

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

17314

34629

51943

69258

86572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13388

26776

40164

53552

66940

<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:

0.384

AC:

58365

AN:

151964

Hom.:

11845

Cov.:

AF XY:

0.392

AC XY:

29118

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.312

AC:

12928

AN:

41440

American (AMR)

AF:

0.446

AC:

6811

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1189

AN:

3464

East Asian (EAS)

AF:

0.746

AC:

3844

AN:

5156

South Asian (SAS)

AF:

0.524

AC:

2527

AN:

4818

European-Finnish (FIN)

AF:

0.396

AC:

4172

AN:

10540

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.377

AC:

25620

AN:

67958

Other (OTH)

AF:

0.382

AC:

806

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1783

3566

5350

7133

8916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.384

Hom.:

47871

Bravo

AF:

0.382

Asia WGS

AF:

0.577

AC:

2003

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Hereditary von Willebrand disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.48

CADD

Benign

(source)

DANN

Benign

0.50

PhyloP100

2.0

Mutation Taster

=68/32

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000010

dbscSNV1_RF

Benign

0.0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over