rs41276736

Variant names:

• chr12-6016550-G-A
• rs41276736
• NM_000552.5:c.5277C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-6016550-G-A
• chr12-6016550-G-C
• chr12-6016550-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000552.5(VWF):​c.5277C>T​(p.Asp1759Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,152 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0079 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (129 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.158
• Publications: 2 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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-6016550-G-A is Benign according to our data. Variant chr12-6016550-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310061.
• BP7: Synonymous conserved (PhyloP=0.158 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00793 (1208/152296) while in subpopulation NFE AF = 0.0138 (937/68024). AF 95% confidence interval is 0.013. There are 7 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.5277C>T	p.Asp1759Asp	synonymous	Exon 30 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.5277C>T	p.Asp1759Asp	synonymous	Exon 30 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.5277C>T	p.Asp1759Asp	synonymous	Exon 31 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+12792C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 1208 AN: 152178 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00795 AC: 1998 AN: 251380 AF XY: 0.00801

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.0121 AC: 17626 AN: 1461856 Hom.: 129 Cov.: 32 AF XY: 0.0117 AC XY: 8490 AN XY: 727228

African (AFR) AF: 0.00158 AC: 53 AN: 33478

American (AMR) AF: 0.00335 AC: 150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00709 AC: 379 AN: 53420

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5738

European-Non Finnish (NFE) AF: 0.0148 AC: 16452 AN: 1112012

Other (OTH) AF: 0.00873 AC: 527 AN: 60392

GnomAD4 genome AF: 0.00793 AC: 1208 AN: 152296 Hom.: 7 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74468

African (AFR) AF: 0.00217 AC: 90 AN: 41568

American (AMR) AF: 0.00647 AC: 99 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0138 AC: 937 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00974 Hom.: 5

Bravo AF: 0.00782

EpiCase AF: 0.0123

EpiControl AF: 0.0111

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.9
DANN	Benign	0.52
PhyloP100		0.16
Mutation Taster		=94/6	polymorphism

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: rs41276736; hg19: chr12-6125716; COSMIC: COSV54635451; COSMIC: COSV54635451;