chr12-6053495-G-A

Variant names:

• chr12-6053495-G-A
• rs2239161
• NM_000552.5:c.1946-712C>T

Variant summary

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

The ENST00000261405.10(VWF):​c.1946-712C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 152,226 control chromosomes in the GnomAD database, including 61,656 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 0.90 (61656 hom., cov: 32)
• Consequence: VWF ENST00000261405.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 3 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261405.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.1946-712C>T		intron	N/A	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.1946-712C>T		intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.420+57020C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136715 AN: 152106 Hom.: 61602 Cov.: 32

Gnomad AFR AF: 0.941

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.865

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.918

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

GnomAD4 genome AF: 0.899 AC: 136827 AN: 152226 Hom.: 61656 Cov.: 32 AF XY: 0.898 AC XY: 66816 AN XY: 74404

African (AFR) AF: 0.941 AC: 39074 AN: 41538

American (AMR) AF: 0.910 AC: 13911 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 3201 AN: 3470

East Asian (EAS) AF: 0.781 AC: 4032 AN: 5160

South Asian (SAS) AF: 0.865 AC: 4169 AN: 4820

European-Finnish (FIN) AF: 0.856 AC: 9075 AN: 10596

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.887 AC: 60333 AN: 68030

Other (OTH) AF: 0.913 AC: 1928 AN: 2112

Alfa AF: 0.888 Hom.: 22324

Bravo AF: 0.906

Asia WGS AF: 0.835 AC: 2905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.75
PhyloP100		0.033
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: rs2239161; hg19: chr12-6162661;