chr3-10141885-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_000551.4(VHL):ā€‹c.38T>Gā€‹(p.Val13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,380,704 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 (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.000013 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -2.10
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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
BP4
Computational evidence support a benign effect (MetaRNN=0.055051833).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkc.38T>G p.Val13Gly missense_variant 1/3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.38T>G p.Val13Gly missense_variant 1/3 NP_001341652.1
VHLNM_198156.3 linkc.38T>G p.Val13Gly missense_variant 1/2 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.108T>G non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.38T>G p.Val13Gly missense_variant 1/31 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000713
AC:
1
AN:
140268
Hom.:
0
AF XY:
0.0000134
AC XY:
1
AN XY:
74528
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000192
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
18
AN:
1380704
Hom.:
0
Cov.:
32
AF XY:
0.0000147
AC XY:
10
AN XY:
678692
show subpopulations
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:
0.0000168
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000349
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 30, 2023This missense variant replaces valine with glycine at codon 13 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 1/140268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 06, 2024This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 13 of the VHL protein (p.Val13Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 526680). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VHL protein function with a negative predictive value of 95%. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 28, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 22, 2023The p.V13G variant (also known as c.38T>G), located in coding exon 1 of the VHL gene, results from a T to G substitution at nucleotide position 38. The valine at codon 13 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is poorly 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
0.051
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
2.1
DANN
Benign
0.34
DEOGEN2
Benign
0.38
T;.
Eigen
Benign
-1.9
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.035
N
LIST_S2
Benign
0.30
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.055
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
-0.34
N;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.87
N;N
REVEL
Benign
0.25
Sift
Benign
0.045
.;D
Sift4G
Benign
0.35
T;T
Polyphen
0.0
B;B
Vest4
0.040
MutPred
0.23
Loss of stability (P = 0.008);Loss of stability (P = 0.008);
MVP
0.74
MPC
0.42
ClinPred
0.089
T
GERP RS
-4.3
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.20
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553619289; hg19: chr3-10183569; API