chr12-6059861-T-C

Variant names:

• chr12-6059861-T-C
• rs980130
• NM_000552.5:c.1534-1817A>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.1534-1817A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,238 control chromosomes in the GnomAD database, including 40,655 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 0.73 (40655 hom., cov: 33)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.807
• Publications: 13 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.1534-1817A>G		intron	N/A	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.1534-1817A>G		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.1534-1817A>G		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.1534-1817A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110694 AN: 152120 Hom.: 40628 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.733

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

GnomAD4 genome AF: 0.728 AC: 110772 AN: 152238 Hom.: 40655 Cov.: 33 AF XY: 0.730 AC XY: 54375 AN XY: 74436

African (AFR) AF: 0.781 AC: 32427 AN: 41544

American (AMR) AF: 0.770 AC: 11783 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2446 AN: 3470

East Asian (EAS) AF: 0.891 AC: 4622 AN: 5188

South Asian (SAS) AF: 0.781 AC: 3765 AN: 4820

European-Finnish (FIN) AF: 0.674 AC: 7149 AN: 10606

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46116 AN: 68000

Other (OTH) AF: 0.732 AC: 1545 AN: 2112

Alfa AF: 0.701 Hom.: 73047

Bravo AF: 0.739

Asia WGS AF: 0.805 AC: 2797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.90
DANN	Benign	0.46
PhyloP100		-0.81
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: rs980130; hg19: chr12-6169027;