rs2228317

Variant names:

• chr12-6046784-C-T
• rs2228317
• NM_000552.5:c.2220G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-6046784-C-T
• chr12-6046784-C-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.2220G>A is a missense variant that replaces methionine with isoleucine at position 740. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1791 (based on 13626/75022 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). This variant has been observed in multiple VWD Type 2M probands in cis with the NM_000552.5(VWF):c.3614G>A (p.Arg1205His) variant, with the phase of the variants confirmed by family segregation analysis (PMID:10959712). This second variant has been classified Pathogenic for VWD Type 2M by the ClinGen VWD VCEP (BP2). The computational predictor REVEL gives a score of 0.059, 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. 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: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA201316/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.053 (706 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (592 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: -0.401
• Publications: 23 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.2220G>A	p.Met740Ile	missense	Exon 17 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.2220G>A	p.Met740Ile	missense	Exon 17 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2220G>A	p.Met740Ile	missense	Exon 18 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2220G>A	p.Met740Ile	missense	Exon 17 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7997 AN: 152188 Hom.: 703 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0482

GnomAD2 exomes AF: 0.0141 AC: 3556 AN: 251326 AF XY: 0.0103

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000739

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00551 AC: 8052 AN: 1461800 Hom.: 592 Cov.: 31 AF XY: 0.00476 AC XY: 3465 AN XY: 727198

African (AFR) AF: 0.182 AC: 6101 AN: 33474

American (AMR) AF: 0.0125 AC: 557 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.000470 AC: 523 AN: 1112008

Other (OTH) AF: 0.0116 AC: 702 AN: 60396

GnomAD4 genome AF: 0.0527 AC: 8019 AN: 152306 Hom.: 706 Cov.: 32 AF XY: 0.0507 AC XY: 3775 AN XY: 74486

African (AFR) AF: 0.181 AC: 7525 AN: 41548

American (AMR) AF: 0.0218 AC: 334 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68032

Other (OTH) AF: 0.0477 AC: 101 AN: 2116

Alfa AF: 0.0211 Hom.: 585

Bravo AF: 0.0587

ESP6500AA AF: 0.181 AC: 796

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0175 AC: 2123

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Hereditary von Willebrand disease (2)
-	-	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	0.15
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.5
DANN	Benign	0.87
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.40
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.059
Sift	Benign	0.045	D
Sift4G	Uncertain	0.031	D
Polyphen		0.010	B
Vest4		0.044
MutPred		0.40		Gain of catalytic residue at M736 (P = 0)
MPC		0.21
ClinPred		0.0020	T
GERP RS		-2.9
Varity_R		0.32
gMVP		0.58
Mutation Taster		=96/4	polymorphism (auto)

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: rs2228317; hg19: chr12-6155950; COSMIC: COSV105844009;