rs1060503557
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000551.4(VHL):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )
Consequence
VHL
NM_000551.4 start_lost
NM_000551.4 start_lost
Scores
2
4
9
Clinical Significance
Conservation
PhyloP100: -0.139
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 Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.1A>G | p.Met1? | start_lost | 1/3 | ENST00000256474.3 | |
VHL | NM_001354723.2 | c.1A>G | p.Met1? | start_lost | 1/3 | ||
VHL | NM_198156.3 | c.1A>G | p.Met1? | start_lost | 1/2 | ||
VHL | NR_176335.1 | n.71A>G | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.1A>G | p.Met1? | start_lost | 1/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 7.23e-7 AC: 1AN: 1383702Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 681222
GnomAD4 exome
AF:
AC:
1
AN:
1383702
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
681222
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease but an alternate initiation codon at Met45 could serve as an in-frame site (Iliopulos et al., 1998; Schoenfeld et al., 1998; Blankenship et al., 1999); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27845047, 33087929, 9751722, 9671762, 10102622) - |
Von Hippel-Lindau syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2017 | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | This sequence change affects the initiator methionine of the VHL mRNA. The next in-frame methionine is located at codon 54. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. 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: 548790). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2020 | The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the VHL gene, results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, however there is an in-frame methionine 54 amino acids downstream which is reported to result in a biologically active isoform known as VHL19 (Iliopoulos O et al. Proc Natl Acad Sci USA.1998 Sep; 95(20):11661-6; Schoenfeld A et al. Proc Natl Acad Sci USA. 1998 Jul; 95(15):8817-22). This amino acid position is well conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift4G
Uncertain
T;D
Polyphen
B;B
Vest4
MutPred
Gain of MoRF binding (P = 0.2114);Gain of MoRF binding (P = 0.2114);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at