3-10146612-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000551.4(VHL):ā€‹c.439A>Gā€‹(p.Ile147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000027 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

1
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10O:1

Conservation

PhyloP100: 1.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a region_of_interest Involved in binding to CCT complex (size 55) in uniprot entity VHL_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) in NM_000551.4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VHLNM_000551.4 linkc.439A>G p.Ile147Val missense_variant Exon 2 of 3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.*18-3175A>G intron_variant Intron 2 of 2 NP_001341652.1
VHLNM_198156.3 linkc.341-3175A>G intron_variant Intron 1 of 1 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.768A>G non_coding_transcript_exon_variant Exon 3 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.439A>G p.Ile147Val missense_variant Exon 2 of 3 1 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251494
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135920
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1461704
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727160
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:
0.0000342
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000547
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Uncertain:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Apr 01, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2
Dec 06, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 23, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with bilateral renal carcinomas (PMID: 20952280); This variant is associated with the following publications: (PMID: 27930734, 25742471, 20952280) -

Hereditary cancer-predisposing syndrome Uncertain:2
Aug 17, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Aug 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.I147V variant (also known as c.439A>G), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 439. The isoleucine at codon 147 is replaced by valine, an amino acid with highly similar properties. This variant has been previously reported in a 34-year-old woman with bilateral renal cancer (Petersson F et al. Ann Diagn Pathol. 2011 Oct;15(5):362-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1Other:1
-
GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 05-30-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Jan 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 147 of the VHL protein (p.Ile147Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clear cell renal cancer (PMID: 20952280). ClinVar contains an entry for this variant (Variation ID: 371833). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 80%. 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 specified Uncertain:1
Mar 28, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in 1 individual; absent from ExAC -

Chuvash polycythemia Uncertain:1
Mar 11, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Uncertain
0.078
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
19
DANN
Benign
0.80
DEOGEN2
Uncertain
0.60
D
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.42
N
LIST_S2
Benign
0.51
T
M_CAP
Pathogenic
0.74
D
MetaRNN
Uncertain
0.49
T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Benign
0.29
N
PrimateAI
Benign
0.45
T
PROVEAN
Benign
0.090
N
REVEL
Uncertain
0.33
Sift4G
Benign
0.94
T
Polyphen
0.0030
B
Vest4
0.44
MutPred
0.64
Gain of loop (P = 0.2754);
MVP
0.82
MPC
0.33
ClinPred
0.045
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.63

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: rs1057517560; hg19: chr3-10188296; COSMIC: COSV99846812; API