12-6057953-G-C

Position:

chr12-6057953-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting

The ENST00000261405.10(VWF):c.1625C>G(p.Ala542Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,708 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A542A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

VWF
ENST00000261405.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8

Conservation

PhyloP100: 1.01

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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=0.046208918).

BS2

High AC in GnomAd4 at 114 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.1625C>G	p.Ala542Gly	missense_variant	14/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.1625C>G	p.Ala542Gly	missense_variant	14/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.1625C>G	p.Ala542Gly	missense_variant	14/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.420+52562C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000719

AC:

180

AN:

250426

Hom.:

AF XY:

0.000700

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00109

AC:

1600

AN:

1461400

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

765

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00131

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000748

AC:

114

AN:

152308

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000589

Hom.:

Bravo

AF:

0.000722

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2023	In the published literature, this variant has been reported in individuals with low VWF and/or Type 1 von Willebrand disease (VWD) co-occurring with another likely pathogenic/pathogenic variant in the VWF gene (PMID: 33556167 (2021)). It has also been reported in an individual with Type 3 VWD in the homozygous state with a homozygous canonical splice variant (PMID: 20801902 (2010), 21251206 (2011), 28971901 (2017)). This variant has also been reported individuals with Type 1, Type 1H, and Type 2A VWD (PMID: 26986123 (2016), 27532107 (2016), 28971901 (2017)), as well as in an individual with a bleeding, thrombotic, or platelet disorder (PMID: 31064749 (2019)). The frequency of this variant in the general population, 0.0015 (4/2642 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2023	BP2, BP4, PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	Observed in the homozygous state in an individual with von Willebrand disease who had an additional homozygous VWF variant in cis (Corrales et al., 2010); Observed in individuals with von Willebrand disease who have a second VWF variant, however it is unknown if these variants are in cis or trans (Sadler et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26986123, 28971901, 31064749, 27532107, 33556167, 20801902) -

Hereditary von Willebrand disease

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine (exon 14). (N) 0251 - Variant is heterozygous. (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Ala542Thr): 1 heterozygote, 0 homozyotes). (N) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (194 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (VWFD 2 motif; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported in multiple patients with type 1, 2A or 3 von Willebrand disease (PMIDs: 26986123, 28971901), however most of them also had another pathogenic VWF variant (PMIDs: 28971901, 27532107, 21251206). It is also reported in ClinVar with conflicting interpretation of pathogenicity. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

von Willebrand disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 14, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 11, 2023

Variant summary: VWF c.1625C>G (p.Ala542Gly) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 250426 control chromosomes (gnomAD). c.1625C>G has been reported in the literature in individuals affected with Von Willebrand Disease (Corrales_2010, Casonato_2016, Veyradier_2016, Sadler_2021, Borras_2017). One patient was reported as putatively compound heterozygous with a pathogenic variant, although other patients were found to have a likely pathogenic variant in cis or without the phase indicated. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20801902, 27532107, 26986123, 33556167, 28971901, 21251206, 31064749). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classified it as uncertain significance (n=4), or pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

VWF-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2022

The VWF c.1625C>G variant is predicted to result in the amino acid substitution p.Ala542Gly. This variant has been reported in patients with von Willebrand disease, but has always been reported in a cis configuration with a splice site variant c.533-2A>G making it unclear whether the missense variant p.Ala542Gly is actually a cause of disease (see Corrales et al. 2010. PubMed ID: 20801902; http://www.hemobase.com/vwf/VWF_Database/Mutations/Mutations.html). This variant has also been reported in studies of VWD patients, but it is unclear whether it is a cause of disease within the studied cohort (Veyradier et al. 2016. PubMed ID: 26986123; Table S2 - Sadler et al. 2021. PubMed ID: 33556167). Additionally, the c.1625C>G (p.Ala542Gly) variant was observed in a cohort of individuals with bleeding, thrombotic and platelet disorders, and reported as likely pathogenic (TGP0672, Supplementary Table 3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.14% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6167119-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

von Willebrand disease type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Dec 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.080

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.55

Vest4

0.20

MVP

0.65

MPC

0.26

ClinPred

0.066

GERP RS

-0.40

Varity_R

0.38

gMVP

0.70

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