rs11612401

Variant names:

• chr12-6027802-G-C
• rs11612401
• NM_000552.5:c.2967+1540C>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.2967+1540C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 150,700 control chromosomes in the GnomAD database, including 3,422 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 0.20 (3422 hom., cov: 29)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144
• Publications: 1 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 (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.2967+1540C>G		intron_variant	Intron 22 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.2967+1540C>G		intron_variant	Intron 22 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.2967+1540C>G		intron_variant	Intron 22 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-33868C>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30721 AN: 150580 Hom.: 3420 Cov.: 29

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.00157

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.204 AC: 30743 AN: 150700 Hom.: 3422 Cov.: 29 AF XY: 0.199 AC XY: 14608 AN XY: 73512

African (AFR) AF: 0.152 AC: 6212 AN: 40942

American (AMR) AF: 0.175 AC: 2647 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 821 AN: 3462

East Asian (EAS) AF: 0.00157 AC: 8 AN: 5090

South Asian (SAS) AF: 0.111 AC: 526 AN: 4750

European-Finnish (FIN) AF: 0.254 AC: 2610 AN: 10262

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17250 AN: 67806

Other (OTH) AF: 0.200 AC: 419 AN: 2092

Alfa AF: 0.234 Hom.: 552

Bravo AF: 0.196

Asia WGS AF: 0.0650 AC: 228 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	0.94
DANN	Benign	0.53
PhyloP100		0.14
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: rs11612401; hg19: chr12-6136968;