12-6055289-C-T

Variant names:

• chr12-6055289-C-T
• rs12304995
• NM_000552.5:c.1945+1568G>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.1945+1568G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 152,112 control chromosomes in the GnomAD database, including 13,246 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 0.40 (13246 hom., cov: 32)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.48
• Publications: 5 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.1945+1568G>A		intron_variant	Intron 15 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1945+1568G>A		intron_variant	Intron 15 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1945+1568G>A		intron_variant	Intron 15 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+55226G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60732 AN: 151994 Hom.: 13221 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.400 AC: 60799 AN: 152112 Hom.: 13246 Cov.: 32 AF XY: 0.392 AC XY: 29139 AN XY: 74360

African (AFR) AF: 0.565 AC: 23416 AN: 41466

American (AMR) AF: 0.271 AC: 4140 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3468

East Asian (EAS) AF: 0.168 AC: 871 AN: 5174

South Asian (SAS) AF: 0.276 AC: 1327 AN: 4814

European-Finnish (FIN) AF: 0.341 AC: 3605 AN: 10586

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24912 AN: 68008

Other (OTH) AF: 0.387 AC: 818 AN: 2112

Alfa AF: 0.389 Hom.: 2136

Bravo AF: 0.401

Asia WGS AF: 0.274 AC: 957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0050
DANN	Benign	0.73
PhyloP100		-3.5
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: rs12304995; hg19: chr12-6164455;