3-10141885-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_000551.4(VHL):ā€‹c.38T>Cā€‹(p.Val13Ala) 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 1,380,702 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.2e-7 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

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 -1 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=0.040508002).
BP6
Variant 3-10141885-T-C is Benign according to our data. Variant chr3-10141885-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 940981.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkc.38T>C p.Val13Ala missense_variant 1/3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.38T>C p.Val13Ala missense_variant 1/3 NP_001341652.1
VHLNM_198156.3 linkc.38T>C p.Val13Ala missense_variant 1/2 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.108T>C non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.38T>C p.Val13Ala missense_variant 1/31 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.24e-7
AC:
1
AN:
1380702
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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:
9.35e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 24, 2024This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 13 of the VHL protein (p.Val13Ala). 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: 940981). 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 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. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 13, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.047
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.015
DANN
Benign
0.28
DEOGEN2
Benign
0.28
T;.
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.055
N
LIST_S2
Benign
0.31
T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.041
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
-0.34
N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.12
N;N
REVEL
Benign
0.22
Sift
Benign
0.54
.;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;B
Vest4
0.029
MutPred
0.15
Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP
0.78
MPC
0.39
ClinPred
0.052
T
GERP RS
-4.3
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.055
gMVP
0.28

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