chr3-10146602-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_000551.4(VHL):​c.429C>G​(p.Asp143Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D143H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

VHL
NM_000551.4 missense

Scores

2
7
9

Clinical Significance

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

Conservation

PhyloP100: -0.0450

Publications

12 publications found
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]
VHL Gene-Disease associations (from GenCC):
  • pheochromocytoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • von Hippel-Lindau disease
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • renal cell carcinoma
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • autosomal recessive secondary polycythemia not associated with VHL gene
    Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
  • Chuvash polycythemia
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000551.4
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-10146602-C-G is Pathogenic according to our data. Variant chr3-10146602-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 625247.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VHLNM_000551.4 linkc.429C>G p.Asp143Glu missense_variant Exon 2 of 3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNR_176335.1 linkn.758C>G non_coding_transcript_exon_variant Exon 3 of 4
VHLNM_001354723.2 linkc.*18-3185C>G intron_variant Intron 2 of 2 NP_001341652.1
VHLNM_198156.3 linkc.341-3185C>G intron_variant Intron 1 of 1 NP_937799.1 P40337-2A0A0S2Z4K1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.429C>G p.Asp143Glu missense_variant Exon 2 of 3 1 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Dec 30, 2024
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.429C>G variant (also known as p.D143E), located in coding exon 2 of the VHL gene, results from a C to G substitution at nucleotide position 429. The aspartic acid at codon 143 is replaced by glutamic acid, an amino acid with highly similar properties. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Von Hippel-Lindau syndrome Uncertain:1
Aug 01, 2018
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
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
Pathogenic
0.59
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.66
D
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.66
T
M_CAP
Pathogenic
0.51
D
MetaRNN
Uncertain
0.66
D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Benign
0.0
N
PhyloP100
-0.045
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.64
N
REVEL
Uncertain
0.38
Sift4G
Benign
0.10
T
Polyphen
0.021
B
Vest4
0.63
MutPred
0.67
Loss of loop (P = 0.0986);
MVP
0.92
MPC
0.43
ClinPred
0.18
T
GERP RS
-2.7
Varity_R
0.60
gMVP
0.66
Mutation Taster
=75/25
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.23
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.23
Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs773556807; hg19: chr3-10188286; API