3-10141893-G-C

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.46G>C(p.Glu16Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,380,528 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E16A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.755

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 312 pathogenic changes around while only 40 benign (89%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21347854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.46G>C	p.Glu16Gln	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.46G>C	p.Glu16Gln	missense_variant	1/3
VHL	NM_198156.3	c.46G>C	p.Glu16Gln	missense_variant	1/2
VHL	NR_176335.1	n.116G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.46G>C	p.Glu16Gln	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000710 AC: 1 AN: 140774 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 74680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000480

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1380528 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 678530

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: 0.0000258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Invitae

Feb 12, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. This sequence change replaces glutamic acid with glutamine at codon 16 of the VHL protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 02, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2020

The p.E16Q variant (also known as c.46G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 46. The glutamic acid at codon 16 is replaced by glutamine, an amino acid with highly 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.24
Sift4G	Uncertain	0.053	T;D
Polyphen		0.95	P;D
Vest4		0.13
MutPred		0.20		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.97
MPC		0.57
ClinPred		0.19	T
GERP RS		1.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.14
gMVP		0.48

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: rs1060503556; hg19: chr3-10183577;