rs61750615

Variant names:

• chr12-5994484-G-A
• rs61750615
• NM_000552.5:c.6187C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-5994484-G-A
• chr12-5994484-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. BS1 BP5 PP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.6187C>T is a missense variant that replaces proline with serine at position 2063. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.04661 (based on 4353/91066 alleles in the South Asian population, with 145 homozygotes), which is higher than the ClinGen VWD VCEP BS1 threshold of >0.01 (BS1). At least 1 proband harboring the variant in the homozygous state exhibits a history of severe bleeding and a quantitative defect in VWF, consistent with VWD Type 3 (PMID:23354996), however, it is not yet clear whether this phenotype is sufficiently specific to meet PP4. While this variant is also reported to be present in the homozygous state in multiple other affected probands (PMID:23354996), PS4 cannot be considered because BS1 is met. The recombinant p.Pro2063Ser variant in COS-7 cells matches properties of the wild-type recombinant protein, including normal expression, secretion, and multimer formation, inconsistent with a quantitative defect relevant to VWD Type 3 (PMID:19566550). BS3_Supporting is not met because this criterion is considered not applicable to this gene-disease relationship. This variant has been observed in affected cases with an alternate molecular basis for disease, including in VWD Type 3 in cis with either the NM_000552.5(VWF):c.970C>T (p.Arg324Ter) variant (PMID:33550700) or the NM_000552.5(VWF):c.5200C>T (p.Gln1734Ter) variant (PMID:23702511). Both comparison variants have been classified as Pathogenic by the ClinGen VWD VCEP. Three other reported cases with diverse VWD diagnoses harbor this variant as well as a second variant in VWF (PMID:19404524, PMID:21534937, PMID:16985174), however, the comparison variants have not yet been classified by the ClinGen VWD VCEP. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, PP4. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA202650/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0075 (16 hom., cov: 31)
  • Exomes 𝑓: 0.010 (192 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:13 O:1
• Conservation: PhyloP100: 8.27
• Publications: 35 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -4 ACMG points.

• PP4: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.6187C>T	p.Pro2063Ser	missense	Exon 36 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.6187C>T	p.Pro2063Ser	missense	Exon 36 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.6187C>T	p.Pro2063Ser	missense	Exon 37 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+34858C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1139 AN: 152172 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00801

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.0126 AC: 3178 AN: 251442 AF XY: 0.0149

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00825

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0103 AC: 15042 AN: 1461852 Hom.: 192 Cov.: 32 AF XY: 0.0118 AC XY: 8580 AN XY: 727226

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.0111 AC: 495 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 635 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0481 AC: 4148 AN: 86250

European-Finnish (FIN) AF: 0.00125 AC: 67 AN: 53420

Middle Eastern (MID) AF: 0.0260 AC: 150 AN: 5768

European-Non Finnish (NFE) AF: 0.00792 AC: 8806 AN: 1111984

Other (OTH) AF: 0.0116 AC: 701 AN: 60392

GnomAD4 genome AF: 0.00747 AC: 1137 AN: 152290 Hom.: 16 Cov.: 31 AF XY: 0.00777 AC XY: 579 AN XY: 74474

African (AFR) AF: 0.00161 AC: 67 AN: 41566

American (AMR) AF: 0.0125 AC: 192 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0426 AC: 205 AN: 4816

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00801 AC: 545 AN: 68016

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.00871 Hom.: 29

Bravo AF: 0.00741

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.0127 AC: 1545

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0111

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	1	2	Hereditary von Willebrand disease (3)
-	-	3	not specified (3)
-	-	2	von Willebrand disease type 1 (2)
-	-	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	Pathogenic	0.59
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0080	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.027	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.30
MPC		0.92
ClinPred		0.0098	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.85
Mutation Taster		=28/72	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61750615; hg19: chr12-6103650; COSMIC: COSV108805184;