rs199831474

Variant names:

• chr12-6019629-C-T
• rs199831474
• NM_000552.5:c.3789G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-6019629-C-T
• chr12-6019629-C-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_000552.5(VWF):​c.3789G>A​(p.Ser1263Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,611,968 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (6 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -7.15
• Publications: 8 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-6019629-C-T is Benign according to our data. Variant chr12-6019629-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256674.
• BP7: Synonymous conserved (PhyloP=-7.15 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3789G>A	p.Ser1263Ser	synonymous	Exon 28 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3789G>A	p.Ser1263Ser	synonymous	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3789G>A	p.Ser1263Ser	synonymous	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9713G>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00644

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00168 AC: 420 AN: 249542 AF XY: 0.00165

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.00506

Gnomad FIN exome AF: 0.00352

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00137 AC: 2001 AN: 1459764 Hom.: 6 Cov.: 38 AF XY: 0.00149 AC XY: 1081 AN XY: 726230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000209 AC: 7 AN: 33460

American (AMR) AF: 0.000917 AC: 41 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00884 AC: 231 AN: 26126

East Asian (EAS) AF: 0.00376 AC: 147 AN: 39056

South Asian (SAS) AF: 0.00453 AC: 390 AN: 86146

European-Finnish (FIN) AF: 0.00453 AC: 242 AN: 53372

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5750

European-Non Finnish (NFE) AF: 0.000728 AC: 809 AN: 1110860

Other (OTH) AF: 0.00204 AC: 123 AN: 60292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00168 AC: 255 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74400

African (AFR) AF: 0.000313 AC: 13 AN: 41548

American (AMR) AF: 0.00137 AC: 21 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00645 AC: 33 AN: 5114

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4822

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68012

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00159

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	2	not specified (2)
-	-	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	-0.87
CADD	Benign	0.0030
DANN	Benign	0.42
PhyloP100		-7.2
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199831474; hg19: chr12-6128795; COSMIC: COSV54633060;