3-10141951-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000551.4(VHL):​c.104C>A​(p.Ala35Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,392,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000043 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -0.144
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 Uncertain_significance. Variant got 0 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=0.2587483).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkuse as main transcriptc.104C>A p.Ala35Asp missense_variant 1/3 ENST00000256474.3 NP_000542.1
VHLNM_001354723.2 linkuse as main transcriptc.104C>A p.Ala35Asp missense_variant 1/3 NP_001341652.1
VHLNM_198156.3 linkuse as main transcriptc.104C>A p.Ala35Asp missense_variant 1/2 NP_937799.1
VHLNR_176335.1 linkuse as main transcriptn.174C>A non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.104C>A p.Ala35Asp missense_variant 1/31 NM_000551.4 ENSP00000256474 P1P40337-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000431
AC:
6
AN:
1392156
Hom.:
0
Cov.:
32
AF XY:
0.00000292
AC XY:
2
AN XY:
685612
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:
0.00000558
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2023The p.A35D variant (also known as c.104C>A), located in coding exon 1 of the VHL gene, results from a C to A substitution at nucleotide position 104. The alanine at codon 35 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is not 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. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Oct 15, 2021- -
Von Hippel-Lindau syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylJun 06, 2018- -
Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 15, 2023- -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 35 of the VHL protein (p.Ala35Asp). This variant is not present in population databases (gnomAD no frequency). 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: 132707). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL protein function. 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 testingGeneDxSep 25, 2019Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
15
DANN
Benign
0.97
DEOGEN2
Benign
0.37
T;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.84
T;T
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.26
T;T
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
0.69
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.51
N;N
REVEL
Uncertain
0.35
Sift
Uncertain
0.0040
.;D
Sift4G
Uncertain
0.035
D;T
Polyphen
0.91
P;P
Vest4
0.25
MutPred
0.40
Loss of glycosylation at P40 (P = 0.0446);Loss of glycosylation at P40 (P = 0.0446);
MVP
1.0
MPC
1.0
ClinPred
0.68
D
GERP RS
3.9
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.35
gMVP
0.66

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: rs587780536; hg19: chr3-10183635; API