chr12-6019726-T-C

Position:

chr12-6019726-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PM5PP2BP4_StrongBS2_Supporting

The NM_000552.5(VWF):c.3692A>G(p.Asn1231Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,612,190 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1231T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00049 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 10 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 3.00

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity VWF_HUMAN

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-6019726-T-G is described in Lovd as [Pathogenic].

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=0.009687215).

BS2

High AC in GnomAd4 at 75 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.3692A>G	p.Asn1231Ser	missense_variant	28/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.3692A>G	p.Asn1231Ser	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.3692A>G	p.Asn1231Ser	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000539641.1 linkuse as main transcript	n.490A>G		non_coding_transcript_exon_variant	3/3	3
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25792A>G		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00144

AC:

350

AN:

242782

Hom.:

AF XY:

0.00187

AC XY:

247

AN XY:

132372

show subpopulations

Gnomad AFR exome

AF:

0.0000682

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00990

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000315

Gnomad OTH exome

AF:

0.000838

GnomAD4 exome

AF:

0.000789

AC:

1152

AN:

1459982

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

756

AN XY:

726258

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00960

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000813

GnomAD4 genome

AF:

0.000493

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00145

AC:

176

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 10, 2024	The VWF c.3692A>G (p.Asn1231Ser) variant has been reported in the published literature in individuals with type 1 (PMIDs: 28971901 (2017)) and type 2 von Willebrand disease (PMID: 23179108 (2013)). Characterization of the variant showed normal VWF synthesis, secretion and multimers with normal functional parameters (PMIDs: 30488424 (2019), 23179108 (2013)). The frequency of this variant in the general population, 0.0099 (299/30190 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VWF: BP4, BS1 -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2024	Variant summary: VWF c.3692A>G (p.Asn1231Ser) results in a conservative amino acid change located in the von Willebrand factor, VWA N-terminal domain (IPR032361) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 242782 control chromosomes, predominantly at a frequency of 0.0099 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in VWF causing Von Willebrand Disease phenotype.c.3692A>G has been reported in the literature in individuals affected with Von Willebrand Disease (Type 2/ 1H or mild forms) (examples: Ahmad_2013, Van Der Berg_2014, and Borras_2017, Perez-Rodriguez_2021). These reports do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. One publication reports experimental evidence evaluating an impact on protein function. These results demonstrated normal VWF synthesis, secretion and that variant protein forms normal multimers with the authors speculating either a non-causal outcome or a mild-defect (Ahmed_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23179108, 28971901, 24954083, 34494337). ClinVar contains an entry for this variant (Variation ID: 976752). Based on the evidence outlined above, the variant was classified as likely benign. -

von Willebrand disease type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jan 06, 2025

- -

von Willebrand disease type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Hereditary von Willebrand disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

REVEL

Benign

0.020

Sift

Benign

0.17

Sift4G

Benign

0.29

Polyphen

0.0070

Vest4

0.21

MVP

0.32

MPC

0.25

ClinPred

0.011

GERP RS

2.6

Varity_R

0.20

gMVP

0.43

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