rs34230288

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000552.5(VWF):c.6532G>T(p.Ala2178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,996 control chromosomes in the GnomAD database, including 339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 31)

Exomes 𝑓: 0.019 ( 325 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0150

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:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

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=0.008763671).

BP6

Variant 12-5993928-C-A is Benign according to our data. Variant chr12-5993928-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 619942.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr12-5993928-C-A is described in Lovd as [Benign]. Variant chr12-5993928-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1896/152182) while in subpopulation NFE AF= 0.0215 (1462/68006). AF 95% confidence interval is 0.0206. There are 14 homozygotes in gnomad4. There are 848 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1896 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.6532G>T	p.Ala2178Ser	missense_variant	37/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.6532G>T	p.Ala2178Ser	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.6532G>T	p.Ala2178Ser	missense_variant	37/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.427G>T		non_coding_transcript_exon_variant	6/6	4

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1897

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00395

Gnomad FIN

AF:

0.00726

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.0113

AC:

2825

AN:

251010

Hom.:

AF XY:

0.0112

AC XY:

1525

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.00899

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.0192

AC:

28029

AN:

1461814

Hom.:

325

Cov.:

AF XY:

0.0185

AC XY:

13463

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00329

Gnomad4 AMR exome

AF:

0.00454

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00255

Gnomad4 FIN exome

AF:

0.00928

Gnomad4 NFE exome

AF:

0.0233

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0125

AC:

1896

AN:

152182

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

848

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00402

Gnomad4 AMR

AF:

0.00818

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00395

Gnomad4 FIN

AF:

0.00726

Gnomad4 NFE

AF:

0.0215

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0226

AC:

194

ExAC

AF:

0.0113

AC:

1372

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0197

EpiControl

AF:

0.0167

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	VWF: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.6

DANN

Benign

0.80

DEOGEN2

Benign

0.22

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.47

REVEL

Benign

0.12

Sift

Benign

0.58

Sift4G

Benign

0.91

Polyphen

0.0020

Vest4

0.081

MPC

0.25

ClinPred

0.00058

GERP RS

-0.72

Varity_R

0.067

gMVP

0.37

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