rs1642739

Variant names:

• chr3-10153801-A-C
• rs1642739
• NM_000551.4:c.*3836A>C

Variant summary

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

The NM_000551.4(VHL):​c.*3836A>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 151,962 control chromosomes in the GnomAD database, including 60,217 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. The gene VHL is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.89 (60217 hom., cov: 30)
• Consequence: VHL NM_000551.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.892
• Publications: 12 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. 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
	VHL	NM_000551.4	MANE Select	c.*3836A>C		downstream_gene	N/A	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.*4032A>C		downstream_gene	N/A	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.*3836A>C		downstream_gene	N/A	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.*3836A>C		downstream_gene	N/A	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.*3836A>C		downstream_gene	N/A	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.*134A>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135049 AN: 151844 Hom.: 60185 Cov.: 30

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.925

Gnomad EAS AF: 0.884

Gnomad SAS AF: 0.816

Gnomad FIN AF: 0.902

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.880

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.889 AC: 135130 AN: 151962 Hom.: 60217 Cov.: 30 AF XY: 0.891 AC XY: 66155 AN XY: 74280

African (AFR) AF: 0.935 AC: 38806 AN: 41490

American (AMR) AF: 0.864 AC: 13178 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 3212 AN: 3472

East Asian (EAS) AF: 0.884 AC: 4580 AN: 5180

South Asian (SAS) AF: 0.815 AC: 3921 AN: 4810

European-Finnish (FIN) AF: 0.902 AC: 9444 AN: 10466

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59101 AN: 67974

Other (OTH) AF: 0.872 AC: 1838 AN: 2108

Alfa AF: 0.873 Hom.: 113105

Bravo AF: 0.890

Asia WGS AF: 0.830 AC: 2889 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.70
PhyloP100		-0.89

Splicing

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

Other links and lift over

dbSNP: rs1642739; hg19: chr3-10195485;