rs41388848

Variant names:

• chr12-6099452-T-C
• rs41388848
• NM_000552.5:c.533-3868A>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.533-3868A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 152,184 control chromosomes in the GnomAD database, including 1,267 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 0.091 (1267 hom., cov: 31)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• Publications: 2 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.533-3868A>G		intron_variant	Intron 5 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.533-3868A>G		intron_variant	Intron 5 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.533-3868A>G		intron_variant	Intron 5 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000321023.5	n.*592-3868A>G		intron_variant	Intron 6 of 6	1		ENSP00000461331.1
VWF	ENST00000538635.5	n.420+11063A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 13794 AN: 152066 Hom.: 1263 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0813

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

GnomAD4 genome AF: 0.0909 AC: 13830 AN: 152184 Hom.: 1267 Cov.: 31 AF XY: 0.0869 AC XY: 6465 AN XY: 74414

African (AFR) AF: 0.238 AC: 9874 AN: 41490

American (AMR) AF: 0.0561 AC: 857 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3466

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5186

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4828

European-Finnish (FIN) AF: 0.0187 AC: 198 AN: 10602

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2443 AN: 68014

Other (OTH) AF: 0.0805 AC: 170 AN: 2112

Alfa AF: 0.0586 Hom.: 211

Bravo AF: 0.0996

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-0.52
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: rs41388848; hg19: chr12-6208618;