rs2109118

Variant names:

• chr12-6085489-T-C
• rs2109118
• NM_000552.5:c.658-9938A>G

Variant summary

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

The NM_000552.5(VWF):​c.658-9938A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 152,054 control chromosomes in the GnomAD database, including 12,541 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 0.37 (12541 hom., cov: 32)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.658-9938A>G		intron_variant	Intron 6 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.658-9938A>G		intron_variant	Intron 6 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.658-9938A>G		intron_variant	Intron 6 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+25026A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56105 AN: 151936 Hom.: 12547 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.369 AC: 56105 AN: 152054 Hom.: 12541 Cov.: 32 AF XY: 0.368 AC XY: 27313 AN XY: 74316

African (AFR) AF: 0.107 AC: 4426 AN: 41492

American (AMR) AF: 0.433 AC: 6621 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1897 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1551 AN: 5172

South Asian (SAS) AF: 0.354 AC: 1701 AN: 4810

European-Finnish (FIN) AF: 0.446 AC: 4713 AN: 10568

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33809 AN: 67956

Other (OTH) AF: 0.394 AC: 831 AN: 2110

Alfa AF: 0.467 Hom.: 20547

Bravo AF: 0.359

Asia WGS AF: 0.287 AC: 998 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.74
PhyloP100		-0.26
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: rs2109118; hg19: chr12-6194655;