12-6060032-T-C

Variant names:

• chr12-6060032-T-C
• rs980131
• NM_000552.5:c.1534-1988A>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.1534-1988A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 151,284 control chromosomes in the GnomAD database, including 32,032 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 0.65 (32032 hom., cov: 27)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.1534-1988A>G		intron_variant	Intron 13 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1534-1988A>G		intron_variant	Intron 13 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1534-1988A>G		intron_variant	Intron 13 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+50483A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.648 AC: 97899 AN: 151166 Hom.: 32017 Cov.: 27

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.647 AC: 97955 AN: 151284 Hom.: 32032 Cov.: 27 AF XY: 0.652 AC XY: 48193 AN XY: 73866

African (AFR) AF: 0.700 AC: 28791 AN: 41156

American (AMR) AF: 0.724 AC: 11043 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2360 AN: 3460

East Asian (EAS) AF: 0.753 AC: 3851 AN: 5112

South Asian (SAS) AF: 0.698 AC: 3319 AN: 4752

European-Finnish (FIN) AF: 0.609 AC: 6368 AN: 10450

Middle Eastern (MID) AF: 0.750 AC: 219 AN: 292

European-Non Finnish (NFE) AF: 0.590 AC: 40017 AN: 67820

Other (OTH) AF: 0.657 AC: 1375 AN: 2094

Alfa AF: 0.613 Hom.: 114714

Bravo AF: 0.660

Asia WGS AF: 0.692 AC: 2403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.5
DANN	Benign	0.37
PhyloP100		-0.64
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: rs980131; hg19: chr12-6169198;