rs4764478

Variant names:

• chr12-5968959-T-A
• rs4764478
• NM_000552.5:c.7729+252A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000552.5(VWF):​c.7729+252A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,098 control chromosomes in the GnomAD database, including 3,652 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3652 hom., cov: 33)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.7729+252A>T		intron_variant	Intron 45 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.7729+252A>T		intron_variant	Intron 45 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.7729+252A>T		intron_variant	Intron 45 of 51	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32560 AN: 151980 Hom.: 3648 Cov.: 33

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0658

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.214 AC: 32584 AN: 152098 Hom.: 3652 Cov.: 33 AF XY: 0.210 AC XY: 15582 AN XY: 74360

African (AFR) AF: 0.233 AC: 9664 AN: 41474

American (AMR) AF: 0.206 AC: 3152 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 703 AN: 3468

East Asian (EAS) AF: 0.0661 AC: 343 AN: 5186

South Asian (SAS) AF: 0.233 AC: 1122 AN: 4820

European-Finnish (FIN) AF: 0.182 AC: 1924 AN: 10570

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 14999 AN: 67970

Other (OTH) AF: 0.215 AC: 455 AN: 2114

Alfa AF: 0.214 Hom.: 484

Bravo AF: 0.215

Asia WGS AF: 0.175 AC: 613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.81
PhyloP100		-1.7
Mutation Taster		=99/1	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: rs4764478; hg19: chr12-6078125;