12-6078499-G-T

Variant names:

• chr12-6078499-G-T
• rs2238104
• NM_000552.5:c.658-2948C>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.658-2948C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,110 control chromosomes in the GnomAD database, including 10,816 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 0.35 (10816 hom., cov: 32)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.658-2948C>A		intron_variant	Intron 6 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.658-2948C>A		intron_variant	Intron 6 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.658-2948C>A		intron_variant	Intron 6 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+32016C>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52896 AN: 151992 Hom.: 10822 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.348 AC: 52882 AN: 152110 Hom.: 10816 Cov.: 32 AF XY: 0.348 AC XY: 25861 AN XY: 74358

African (AFR) AF: 0.137 AC: 5678 AN: 41510

American (AMR) AF: 0.306 AC: 4684 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1542 AN: 3470

East Asian (EAS) AF: 0.326 AC: 1683 AN: 5164

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4824

European-Finnish (FIN) AF: 0.483 AC: 5099 AN: 10556

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31322 AN: 67974

Other (OTH) AF: 0.348 AC: 734 AN: 2112

Alfa AF: 0.445 Hom.: 15661

Bravo AF: 0.329

Asia WGS AF: 0.279 AC: 971 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.8
DANN	Benign	0.70
PhyloP100		0.24
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: rs2238104; hg19: chr12-6187665;