chr12-6072469-G-C

Variant names:

• chr12-6072469-G-C
• rs55907031
• NM_000552.5:c.998-27C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000552.5(VWF):​c.998-27C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 1,419,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.998-27C>G		intron_variant	Intron 8 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.998-27C>G		intron_variant	Intron 8 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.998-27C>G		intron_variant	Intron 8 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+38046C>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246360 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000705 AC: 10 AN: 1419062 Hom.: 0 Cov.: 25 AF XY: 0.00000424 AC XY: 3 AN XY: 708328

African (AFR) AF: 0.00 AC: 0 AN: 32684

American (AMR) AF: 0.0000224 AC: 1 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000559 AC: 6 AN: 1073632

Other (OTH) AF: 0.0000169 AC: 1 AN: 59006

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 519

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.46
DANN	Benign	0.52
PhyloP100		0.025

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs55907031; hg19: chr12-6181635;