rs2239138

Variant names:

• chr12-5973392-A-T
• rs2239138
• NM_000552.5:c.7438-1683T>A

Variant summary

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

The NM_000552.5(VWF):​c.7438-1683T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 152,126 control chromosomes in the GnomAD database, including 34,525 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 0.67 (34525 hom., cov: 33)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.7438-1683T>A		intron_variant	Intron 43 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.7438-1683T>A		intron_variant	Intron 43 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.7438-1683T>A		intron_variant	Intron 43 of 51	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101295 AN: 152008 Hom.: 34498 Cov.: 33

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.697

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

GnomAD4 genome AF: 0.666 AC: 101367 AN: 152126 Hom.: 34525 Cov.: 33 AF XY: 0.661 AC XY: 49165 AN XY: 74356

African (AFR) AF: 0.753 AC: 31246 AN: 41494

American (AMR) AF: 0.610 AC: 9328 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2617 AN: 3472

East Asian (EAS) AF: 0.284 AC: 1467 AN: 5170

South Asian (SAS) AF: 0.547 AC: 2634 AN: 4818

European-Finnish (FIN) AF: 0.649 AC: 6870 AN: 10578

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44932 AN: 67984

Other (OTH) AF: 0.693 AC: 1463 AN: 2110

Alfa AF: 0.664 Hom.: 4201

Bravo AF: 0.668

Asia WGS AF: 0.450 AC: 1572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.7
DANN	Benign	0.53
PhyloP100		1.4
Mutation Taster		=100/0	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: rs2239138; hg19: chr12-6082558;