rs1057517592
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4
The NM_000551.4(VHL):c.83_100dup(p.Asp28_Ser33dup) variant causes a inframe insertion 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
VHL
NM_000551.4 inframe_insertion
NM_000551.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.09
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_pathogenic. Variant got 6 ACMG points.
PM1
?
In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 311 pathogenic changes around while only 39 benign (89%) in NM_000551.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000551.4.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.83_100dup | p.Asp28_Ser33dup | inframe_insertion | 1/3 | ENST00000256474.3 | |
VHL | NM_001354723.2 | c.83_100dup | p.Asp28_Ser33dup | inframe_insertion | 1/3 | ||
VHL | NM_198156.3 | c.83_100dup | p.Asp28_Ser33dup | inframe_insertion | 1/2 | ||
VHL | NR_176335.1 | n.153_170dup | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.83_100dup | p.Asp28_Ser33dup | inframe_insertion | 1/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Von Hippel-Lindau syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 09, 2016 | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This variant, c.83_100dup, results in the insertion of 6 amino acid(s) of the VHL protein (p.Asp28_Ser33dup), but otherwise preserves the integrity of the reading frame. 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: 371945). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at