rs779805

Variant names:

• chr3-10141653-G-A
• rs779805
• NM_000551.4:c.-195G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10141653-G-A
• chr3-10141653-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000551.4(VHL):​c.-195G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 598,664 control chromosomes in the GnomAD database, including 129,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27770 hom., cov: 33)
  • Exomes 𝑓: 0.67 (102174 hom.)
• Consequence: VHL NM_000551.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.395
• Publications: 42 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-10141653-G-A is Benign according to our data. Variant chr3-10141653-G-A is described in ClinVar as Benign. ClinVar VariationId is 342397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.-195G>A		upstream_gene_variant		ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.-195G>A		upstream_gene_variant			NP_001341652.1
VHL	NM_198156.3	c.-195G>A		upstream_gene_variant			NP_937799.1
VHL	NR_176335.1	n.-125G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.-195G>A		upstream_gene_variant		1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86405 AN: 151902 Hom.: 27755 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.740

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.670 AC: 299218 AN: 446648 Hom.: 102174 Cov.: 5 AF XY: 0.664 AC XY: 155049 AN XY: 233610

African (AFR) AF: 0.252 AC: 2345 AN: 9314

American (AMR) AF: 0.642 AC: 9405 AN: 14642

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 9418 AN: 12802

East Asian (EAS) AF: 0.734 AC: 19672 AN: 26808

South Asian (SAS) AF: 0.544 AC: 23846 AN: 43836

European-Finnish (FIN) AF: 0.749 AC: 22116 AN: 29534

Middle Eastern (MID) AF: 0.624 AC: 1200 AN: 1922

European-Non Finnish (NFE) AF: 0.689 AC: 194551 AN: 282216

Other (OTH) AF: 0.652 AC: 16665 AN: 25574

GnomAD4 genome AF: 0.569 AC: 86449 AN: 152016 Hom.: 27770 Cov.: 33 AF XY: 0.576 AC XY: 42806 AN XY: 74294

African (AFR) AF: 0.244 AC: 10098 AN: 41460

American (AMR) AF: 0.652 AC: 9975 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 2571 AN: 3472

East Asian (EAS) AF: 0.788 AC: 4069 AN: 5162

South Asian (SAS) AF: 0.558 AC: 2690 AN: 4820

European-Finnish (FIN) AF: 0.761 AC: 8012 AN: 10530

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.692 AC: 47025 AN: 67972

Other (OTH) AF: 0.599 AC: 1262 AN: 2108

Alfa AF: 0.644 Hom.: 40256

Bravo AF: 0.548

Asia WGS AF: 0.655 AC: 2277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22084938) -

Von Hippel-Lindau syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.3
DANN	Benign	0.82
PhyloP100		0.40
PromoterAI		-0.081	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779805; hg19: chr3-10183337;