12-6019726-T-G

Position:

• chr12-6019726-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP5 BS1

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.3692A>C is a missense variant encoding a substitution of asparagine by threonine at position 1231. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID:8134377, PMID:17190853, PMID:31064749, PMID:16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID:8134377, PMID:2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least two control individuals (PMID:22197721). REVEL gives a score of 0.069, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID:16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01138 (based on 900/74802 alleles in the African/African-American population, including 7 homozygotes), which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228435/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:6 O:1
• Conservation: PhyloP100: 3.00

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3692A>C	p.Asn1231Thr	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3692A>C	p.Asn1231Thr	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3692A>C	p.Asn1231Thr	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000539641.1	n.490A>C		non_coding_transcript_exon_variant	3/3	3
VWF	ENST00000538635.5	n.421-25792A>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 757 AN: 152082 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00914

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00136 AC: 329 AN: 242782 Hom.: 2 AF XY: 0.00132 AC XY: 175 AN XY: 132372

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.000877

Gnomad SAS exome AF: 0.00321

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000879

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00180 AC: 2632 AN: 1458198 Hom.: 9 Cov.: 38 AF XY: 0.00199 AC XY: 1444 AN XY: 725322

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.000764

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.00607

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00501 AC: 762 AN: 152200 Hom.: 5 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74440

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00915

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000901 Hom.: 0

Bravo AF: 0.00519

ExAC AF: 0.00194 AC: 235

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 17, 2023	- -

Hereditary von Willebrand disease Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely benign, reviewed by expert panel	curation	ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	Aug 12, 2024	NM_000552.5(VWF):c.3692A>C is a missense variant encoding a substitution of asparagine by threonine at position 1231. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID: 8134377, PMID: 17190853, PMID: 31064749, PMID: 16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID: 8134377, PMID: 2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least two control individuals (PMID: 22197721). REVEL gives a score of 0.069, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID: 16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01138 (based on 900/74802 alleles in the African/African-American population, including 7 homozygotes), which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. -

Abnormality of coagulation Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.069
Sift	Benign	0.33	T
Sift4G	Benign	0.52	T
Polyphen		0.019	B
Vest4		0.48
MVP		0.52
MPC		0.34
ClinPred		0.020	T
GERP RS		2.6
Varity_R		0.22
gMVP		0.55

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

Other links and lift over

dbSNP: rs61749368; hg19: chr12-6128892; COSMIC: COSV54633712;