NM_000552.5:c.3686T>G

Variant names:

• chr12-6019732-A-C
• rs61749367
• NM_000552.5:c.3686T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP5 BS1 BP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.3686T>G is a missense variant encoding a substitution of valine by glycine at position 1229. 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 three control individuals (PMID:22197721). The computational predictor REVEL gives a score of 0.149, 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 0.01529 (based on 1200/74796 alleles, with 10 homozygotes) in the African/African-American population, 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/CA228433/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (11 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:7 O:1
• Conservation: PhyloP100: 3.55
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.3686T>G	p.Val1229Gly	missense	Exon 28 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3686T>G	p.Val1229Gly	missense	Exon 28 of 52	ENSP00000261405.5
	VWF	ENST00000539641.1	TSL:3	n.484T>G		non_coding_transcript_exon	Exon 3 of 3
	VWF	ENST00000538635.5	TSL:4	n.421-25798T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152206 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00157 AC: 380 AN: 241848 AF XY: 0.00158

Gnomad AFR exome AF: 0.00983

Gnomad AMR exome AF: 0.000702

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000855

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00180 AC: 2626 AN: 1458030 Hom.: 11 Cov.: 38 AF XY: 0.00196 AC XY: 1421 AN XY: 725198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0137 AC: 456 AN: 33230

American (AMR) AF: 0.00108 AC: 48 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26058

East Asian (EAS) AF: 0.000731 AC: 29 AN: 39684

South Asian (SAS) AF: 0.00515 AC: 442 AN: 85742

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53248

Middle Eastern (MID) AF: 0.00421 AC: 24 AN: 5706

European-Non Finnish (NFE) AF: 0.00129 AC: 1427 AN: 1109630

Other (OTH) AF: 0.00317 AC: 191 AN: 60216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00641 AC: 977 AN: 152324 Hom.: 6 Cov.: 32 AF XY: 0.00608 AC XY: 453 AN XY: 74492

African (AFR) AF: 0.0179 AC: 744 AN: 41566

American (AMR) AF: 0.00255 AC: 39 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00620 Hom.: 3

Bravo AF: 0.00703

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00204 AC: 247

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	1	1	Hereditary von Willebrand disease (2)
-	-	2	not specified (2)
-	1	-	Abnormality of coagulation (1)
-	1	-	von Willebrand disease type 1 (1)
-	1	-	von Willebrand disease type 2 (1)
-	1	-	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.35
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.020	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.0	N
PhyloP100		3.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.37
MPC		0.35
ClinPred		0.0028	T
GERP RS		4.9
Varity_R		0.20
gMVP		0.81
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs61749367; hg19: chr12-6128898; COSMIC: COSV54633722;