rs2229446

Positions:

chr12-5993906-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000261405.10(VWF):c.6554G>A(p.Arg2185Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0111 in 1,613,710 control chromosomes in the GnomAD database, including 1,462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2185W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.056 ( 804 hom., cov: 31)

Exomes 𝑓: 0.0064 ( 658 hom. )

Consequence

VWF
ENST00000261405.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 4.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000261405.10

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019934475).

BP6

Variant 12-5993906-C-T is Benign according to our data. Variant chr12-5993906-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 100443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5993906-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.6554G>A	p.Arg2185Gln	missense_variant	37/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.6554G>A	p.Arg2185Gln	missense_variant	37/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.6554G>A	p.Arg2185Gln	missense_variant	37/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.449G>A		non_coding_transcript_exon_variant	6/6	4

Frequencies

GnomAD3 genomes

AF:

0.0562

AC:

8542

AN:

151896

Hom.:

806

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0246

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00499

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.0465

GnomAD3 exomes

AF:

0.0156

AC:

3897

AN:

250554

Hom.:

341

AF XY:

0.0120

AC XY:

1629

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.00488

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.00735

GnomAD4 exome

AF:

0.00637

AC:

9309

AN:

1461696

Hom.:

658

Cov.:

AF XY:

0.00573

AC XY:

4163

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.00467

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00413

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000812

Gnomad4 OTH exome

AF:

0.0136

GnomAD4 genome

AF:

0.0563

AC:

8556

AN:

152014

Hom.:

804

Cov.:

AF XY:

0.0535

AC XY:

3975

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.0246

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00479

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.0460

Alfa

AF:

0.0125

Hom.:

238

Bravo

AF:

0.0640

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.199

AC:

877

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.0194

AC:

2352

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2022	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary von Willebrand disease

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

von Willebrand disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

von Willebrand disease type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

MutationTaster

Benign

5.4e-7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.37

Sift

Benign

0.055

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.081

MPC

0.90

ClinPred

0.031

GERP RS

5.3

Varity_R

0.40

gMVP

0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over