chr12-6019726-T-G

Variant names:

• chr12-6019726-T-G
• rs61749368
• NM_000552.5:c.3692A>C

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.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:7 O:1
• Conservation: PhyloP100: 3.00
• Publications: 17 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.3692A>C	p.Asn1231Thr	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.3692A>C	p.Asn1231Thr	missense	Exon 28 of 52	ENSP00000261405.5
	VWF	ENST00000895679.1		c.3692A>C	p.Asn1231Thr	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9616A>C		intron	N/A	ENSP00000565739.1

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

GnomAD2 exomes AF: 0.00136 AC: 329 AN: 242782 AF XY: 0.00132

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 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

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

African (AFR) AF: 0.0106 AC: 352 AN: 33278

American (AMR) AF: 0.000764 AC: 34 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26074

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39680

South Asian (SAS) AF: 0.00607 AC: 521 AN: 85808

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53288

Middle Eastern (MID) AF: 0.00454 AC: 26 AN: 5724

European-Non Finnish (NFE) AF: 0.00134 AC: 1484 AN: 1109622

Other (OTH) AF: 0.00296 AC: 178 AN: 60214

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

African (AFR) AF: 0.0132 AC: 548 AN: 41524

American (AMR) AF: 0.00124 AC: 19 AN: 15298

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

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.00915 AC: 44 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 67990

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.000901 Hom.: 0

Bravo AF: 0.00519

ExAC AF: 0.00194 AC: 235

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.0
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
Mutation Taster		=89/11	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: rs61749368; hg19: chr12-6128892; COSMIC: COSV54633712;