rs786204065

Positions:

• chr3-10141876-A-G
• chr3-10141876-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000551.4(VHL):​c.29A>G​(p.Glu10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.456

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107682854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.29A>G	p.Glu10Gly	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.29A>G	p.Glu10Gly	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.29A>G	p.Glu10Gly	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.99A>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.29A>G	p.Glu10Gly	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381284 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 679158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2020

This sequence change replaces glutamic acid with glycine at codon 10 of the VHL protein (p.Glu10Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with VHL-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2024

The p.E10G variant (also known as c.29A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 29. The glutamic acid at codon 10 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.27		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.92
MPC		0.65
ClinPred		0.31	T
GERP RS		1.4
Varity_R		0.21
gMVP		0.43

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: rs786204065; hg19: chr3-10183560; COSMIC: COSV56568464; COSMIC: COSV56568464;