chr12-5948811-G-A

Variant names:

• chr12-5948811-G-A
• rs7976955
• NM_000552.5:c.*204C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000552.5(VWF):​c.*204C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 632,192 control chromosomes in the GnomAD database, including 10,443 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2563 hom., cov: 33)
  • Exomes 𝑓: 0.17 (7880 hom.)
• Consequence: VWF NM_000552.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.*204C>T		downstream_gene_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.*204C>T		downstream_gene_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.*204C>T		downstream_gene_variant		1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27003 AN: 152076 Hom.: 2557 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.172 AC: 82764 AN: 479996 Hom.: 7880 AF XY: 0.178 AC XY: 45150 AN XY: 253402

African (AFR) AF: 0.213 AC: 2915 AN: 13672

American (AMR) AF: 0.133 AC: 3460 AN: 25978

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 2352 AN: 14828

East Asian (EAS) AF: 0.0233 AC: 709 AN: 30374

South Asian (SAS) AF: 0.261 AC: 13225 AN: 50744

European-Finnish (FIN) AF: 0.138 AC: 3988 AN: 28948

Middle Eastern (MID) AF: 0.216 AC: 443 AN: 2054

European-Non Finnish (NFE) AF: 0.178 AC: 50991 AN: 286618

Other (OTH) AF: 0.175 AC: 4681 AN: 26780

GnomAD4 genome AF: 0.178 AC: 27032 AN: 152196 Hom.: 2563 Cov.: 33 AF XY: 0.174 AC XY: 12944 AN XY: 74420

African (AFR) AF: 0.218 AC: 9048 AN: 41504

American (AMR) AF: 0.138 AC: 2114 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3472

East Asian (EAS) AF: 0.0291 AC: 151 AN: 5188

South Asian (SAS) AF: 0.247 AC: 1194 AN: 4828

European-Finnish (FIN) AF: 0.131 AC: 1391 AN: 10606

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11914 AN: 67984

Other (OTH) AF: 0.162 AC: 343 AN: 2112

Alfa AF: 0.117 Hom.: 270

Bravo AF: 0.180

Asia WGS AF: 0.136 AC: 478 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.19
DANN	Benign	0.62
PhyloP100		-1.6
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7976955; hg19: chr12-6057977;