rs2854871

Variant names:

• chr12-6023913-T-C
• rs2854871
• NM_000552.5:c.3223-126A>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.3223-126A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,010,306 control chromosomes in the GnomAD database, including 4,098 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 0.089 (617 hom., cov: 32)
  • Exomes 𝑓: 0.085 (3481 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.3223-126A>G		intron_variant	Intron 24 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3223-126A>G		intron_variant	Intron 24 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3223-126A>G		intron_variant	Intron 24 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-29979A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13537 AN: 152192 Hom.: 618 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0656

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0935

GnomAD4 exome AF: 0.0853 AC: 73204 AN: 857996 Hom.: 3481 AF XY: 0.0884 AC XY: 39082 AN XY: 442222

African (AFR) AF: 0.108 AC: 2085 AN: 19368

American (AMR) AF: 0.0506 AC: 1754 AN: 34676

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 1082 AN: 21632

East Asian (EAS) AF: 0.110 AC: 3678 AN: 33364

South Asian (SAS) AF: 0.152 AC: 10296 AN: 67550

European-Finnish (FIN) AF: 0.0751 AC: 3666 AN: 48820

Middle Eastern (MID) AF: 0.0794 AC: 239 AN: 3010

European-Non Finnish (NFE) AF: 0.0797 AC: 47024 AN: 589710

Other (OTH) AF: 0.0848 AC: 3380 AN: 39866

GnomAD4 genome AF: 0.0889 AC: 13540 AN: 152310 Hom.: 617 Cov.: 32 AF XY: 0.0901 AC XY: 6708 AN XY: 74476

African (AFR) AF: 0.106 AC: 4424 AN: 41562

American (AMR) AF: 0.0655 AC: 1003 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 175 AN: 3472

East Asian (EAS) AF: 0.121 AC: 626 AN: 5180

South Asian (SAS) AF: 0.154 AC: 741 AN: 4822

European-Finnish (FIN) AF: 0.0753 AC: 800 AN: 10628

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0807 AC: 5490 AN: 68028

Other (OTH) AF: 0.0930 AC: 196 AN: 2108

Alfa AF: 0.0778 Hom.: 125

Bravo AF: 0.0875

Asia WGS AF: 0.116 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.026
DANN	Benign	0.83
PhyloP100		-1.9
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: rs2854871; hg19: chr12-6133079;