rs78353028

Variant names:

• chr12-5952509-G-A
• rs78353028
• NM_000552.5:c.7997C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.7997C>T is a missense variant that substitutes threonine for methionine at position 2666. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.06826 (based on 5238/74998 alleles in the African/African American population) which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). While this variant has been observed in healthy control individuals (PMID:22197721), BS2 is not being used due to penetrance issues. The computational predictor REVEL gives a score of 0.027, 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 von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6401422/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.020 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (95 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely benign reviewed by expert panel B:10
• Conservation: PhyloP100: 0.519
• Publications: 6 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 -5 ACMG points.

• BP4: 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.7997C>T	p.Thr2666Met	missense	Exon 49 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.7997C>T	p.Thr2666Met	missense	Exon 49 of 52	ENSP00000261405.5
	VWF	ENST00000612016.1	TSL:5	n.406C>T		non_coding_transcript_exon	Exon 2 of 3
	VWF	ENST00000621700.1	TSL:3	n.315C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3100 AN: 152166 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00513 AC: 1290 AN: 251334 AF XY: 0.00388

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00206 AC: 3012 AN: 1461530 Hom.: 95 Cov.: 32 AF XY: 0.00178 AC XY: 1291 AN XY: 727094

African (AFR) AF: 0.0691 AC: 2313 AN: 33474

American (AMR) AF: 0.00427 AC: 191 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86230

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53372

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111796

Other (OTH) AF: 0.00487 AC: 294 AN: 60380

GnomAD4 genome AF: 0.0204 AC: 3099 AN: 152284 Hom.: 96 Cov.: 32 AF XY: 0.0195 AC XY: 1454 AN XY: 74484

African (AFR) AF: 0.0704 AC: 2925 AN: 41524

American (AMR) AF: 0.00817 AC: 125 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68044

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00748 Hom.: 75

Bravo AF: 0.0236

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0685 AC: 302

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00605 AC: 735

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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)
-	-	1	VWF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.46
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.52
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.027
Sift	Benign	0.21	T
Sift4G	Benign	0.15	T
Polyphen		0.0090	B
Vest4		0.065
MVP		0.48
MPC		0.28
ClinPred		0.0040	T
GERP RS		0.38
Varity_R		0.033
gMVP		0.73
Mutation Taster		=90/10	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: rs78353028; hg19: chr12-6061675;