rs2885752

Variant names:

• chr12-6023618-C-T
• rs2885752
• NM_000552.5:c.3379+13G>A

Variant summary

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

The ENST00000261405.10(VWF):​c.3379+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,613,616 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (81 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (84 hom.)
• Consequence: VWF ENST00000261405.10 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.136
• Publications: 0 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=-0.81).
• BP6: Variant 12-6023618-C-T is Benign according to our data. Variant chr12-6023618-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0595 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.3379+13G>A		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.3379+13G>A		intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-29684G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2746 AN: 152232 Hom.: 81 Cov.: 31

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00499 AC: 1241 AN: 248832 AF XY: 0.00388

Gnomad AFR exome AF: 0.0608

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00728

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000454

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00226 AC: 3297 AN: 1461266 Hom.: 84 Cov.: 32 AF XY: 0.00214 AC XY: 1559 AN XY: 726852

African (AFR) AF: 0.0634 AC: 2122 AN: 33478

American (AMR) AF: 0.00322 AC: 144 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 178 AN: 25992

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000721 AC: 62 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00991 AC: 57 AN: 5752

European-Non Finnish (NFE) AF: 0.000375 AC: 417 AN: 1111922

Other (OTH) AF: 0.00524 AC: 316 AN: 60354

GnomAD4 genome AF: 0.0181 AC: 2755 AN: 152350 Hom.: 81 Cov.: 31 AF XY: 0.0179 AC XY: 1331 AN XY: 74488

African (AFR) AF: 0.0615 AC: 2557 AN: 41564

American (AMR) AF: 0.00732 AC: 112 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68042

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00975 Hom.: 4

Bravo AF: 0.0195

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary von Willebrand disease (1)
-	-	1	not specified (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (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	-0.81
CADD	Benign	6.6
DANN	Benign	0.51
PhyloP100		-0.14
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: rs2885752; hg19: chr12-6132784;