rs216325

Variant names:

• chr12-6036363-G-A
• rs216325
• NM_000552.5:c.2546+25C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-6036363-G-A
• chr12-6036363-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.2546+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,609,928 control chromosomes in the GnomAD database, including 365,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38221 hom., cov: 33)
  • Exomes 𝑓: 0.67 (327528 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.15
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-6036363-G-A is Benign according to our data. Variant chr12-6036363-G-A is described in ClinVar as Benign. ClinVar VariationId is 256661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 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.2546+25C>T		intron	N/A	NP_000543.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.2546+25C>T		intron	N/A	ENSP00000261405.5
	VWF	ENST00000895679.1		c.2546+25C>T		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2546+25C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107340 AN: 152014 Hom.: 38193 Cov.: 33

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.719

GnomAD2 exomes AF: 0.706 AC: 176978 AN: 250800 AF XY: 0.703

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.696

GnomAD4 exome AF: 0.668 AC: 974067 AN: 1457796 Hom.: 327528 Cov.: 32 AF XY: 0.670 AC XY: 485977 AN XY: 725516

African (AFR) AF: 0.768 AC: 25673 AN: 33408

American (AMR) AF: 0.795 AC: 35523 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 18451 AN: 26110

East Asian (EAS) AF: 0.794 AC: 31490 AN: 39674

South Asian (SAS) AF: 0.740 AC: 63753 AN: 86164

European-Finnish (FIN) AF: 0.638 AC: 34011 AN: 53296

Middle Eastern (MID) AF: 0.737 AC: 4165 AN: 5648

European-Non Finnish (NFE) AF: 0.650 AC: 719995 AN: 1108536

Other (OTH) AF: 0.681 AC: 41006 AN: 60250

GnomAD4 genome AF: 0.706 AC: 107417 AN: 152132 Hom.: 38221 Cov.: 33 AF XY: 0.711 AC XY: 52860 AN XY: 74386

African (AFR) AF: 0.774 AC: 32120 AN: 41512

American (AMR) AF: 0.745 AC: 11384 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2450 AN: 3472

East Asian (EAS) AF: 0.790 AC: 4085 AN: 5174

South Asian (SAS) AF: 0.762 AC: 3672 AN: 4820

European-Finnish (FIN) AF: 0.648 AC: 6851 AN: 10578

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44483 AN: 67966

Other (OTH) AF: 0.716 AC: 1513 AN: 2114

Alfa AF: 0.677 Hom.: 45512

Bravo AF: 0.716

Asia WGS AF: 0.770 AC: 2676 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 2 (1)
-	-	1	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.012
DANN	Benign	0.75
PhyloP100		-4.2
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: rs216325; hg19: chr12-6145529; COSMIC: COSV107218078;