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. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 310061.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr12-6016550-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1208 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.5277C>T	p.Asp1759Asp	synonymous_variant	Exon 30 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5277C>T	p.Asp1759Asp	synonymous_variant	Exon 30 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5277C>T	p.Asp1759Asp	synonymous_variant	Exon 30 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-22616C>T		intron_variant	Intron 5 of 5	4

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

GnomAD3 exomes AF: 0.00795 AC: 1998 AN: 251380 Hom.: 18 AF XY: 0.00801 AC XY: 1089 AN XY: 135880

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00709

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.00873

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

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00987 Hom.: 5

Bravo AF: 0.00782

EpiCase AF: 0.0123

EpiControl AF: 0.0111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	VWF: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 08, 2020	- -

Hereditary von Willebrand disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.9
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

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