rs535693463

Variant names:

• chr12-6022852-A-G
• rs535693463
• NM_000552.5:c.3426T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.3426T>C​(p.Cys1142Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (618 hom., cov: 13)
  • Exomes 𝑓: 0.0082 (273 hom.)
  • Failed GnomAD Quality Control
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.546
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-6022852-A-G is Benign according to our data. Variant chr12-6022852-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.546 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.3426T>C	p.Cys1142Cys	synonymous	Exon 26 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3426T>C	p.Cys1142Cys	synonymous	Exon 26 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-28918T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 5823 AN: 106910 Hom.: 615 Cov.: 13

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0158

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000240

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0203

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0647

GnomAD2 exomes AF: 0.0256 AC: 1391 AN: 54300 AF XY: 0.0228

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00988

GnomAD4 exome AF: 0.00821 AC: 3574 AN: 435144 Hom.: 273 Cov.: 3 AF XY: 0.00700 AC XY: 1612 AN XY: 230312

African (AFR) AF: 0.209 AC: 2527 AN: 12112

American (AMR) AF: 0.0187 AC: 344 AN: 18444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13226

East Asian (EAS) AF: 0.000102 AC: 3 AN: 29318

South Asian (SAS) AF: 0.000487 AC: 22 AN: 45192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26836

Middle Eastern (MID) AF: 0.0148 AC: 28 AN: 1896

European-Non Finnish (NFE) AF: 0.000935 AC: 246 AN: 263022

Other (OTH) AF: 0.0161 AC: 404 AN: 25098

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0546 AC: 5844 AN: 107000 Hom.: 618 Cov.: 13 AF XY: 0.0543 AC XY: 2672 AN XY: 49166

African (AFR) AF: 0.207 AC: 5408 AN: 26094

American (AMR) AF: 0.0298 AC: 274 AN: 9206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2880

East Asian (EAS) AF: 0.000241 AC: 1 AN: 4152

South Asian (SAS) AF: 0.00 AC: 0 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5782

Middle Eastern (MID) AF: 0.0219 AC: 6 AN: 274

European-Non Finnish (NFE) AF: 0.00104 AC: 56 AN: 53882

Other (OTH) AF: 0.0640 AC: 87 AN: 1360

Alfa AF: 0.0514 Hom.: 64

Bravo AF: 0.0735

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary von Willebrand disease (1)
-	-	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	-0.59
CADD	Benign	0.73
DANN	Benign	0.48
PhyloP100		-0.55
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs535693463; hg19: chr12-6132018;