3-10141782-CTCCGCCCCGCG-CTCCGCCCCGCGTCCGCCCCGCG
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_000551.4(VHL):c.-61_-51dupCCCCGCGTCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,518,350 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00045 ( 7 hom. )
Consequence
VHL
NM_000551.4 5_prime_UTR
NM_000551.4 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.938
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 Benign. Variant got -9 ACMG points.
BP6
Variant 3-10141782-C-CTCCGCCCCGCG is Benign according to our data. Variant chr3-10141782-C-CTCCGCCCCGCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517152.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000276 (42/152348) while in subpopulation SAS AF= 0.00331 (16/4834). AF 95% confidence interval is 0.00208. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 7 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | c.-61_-51dupCCCCGCGTCCG | 5_prime_UTR_variant | Exon 1 of 3 | ENST00000256474.3 | NP_000542.1 | ||
| VHL | NM_001354723.2 | c.-61_-51dupCCCCGCGTCCG | 5_prime_UTR_variant | Exon 1 of 3 | NP_001341652.1 | |||
| VHL | NM_198156.3 | c.-61_-51dupCCCCGCGTCCG | 5_prime_UTR_variant | Exon 1 of 2 | NP_937799.1 | |||
| VHL | NR_176335.1 | n.10_20dupCCCCGCGTCCG | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Frequencies
GnomAD3 genomes 0.000282 AC: 43AN: 152230Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.000452 AC: 618AN: 1366002Hom.: 7 Cov.: 29 AF XY: 0.000565 AC XY: 381AN XY: 674038
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GnomAD4 genome 0.000276 AC: 42AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 07, 2021 | DNA sequence analysis of the VHL gene demonstrated an 11 base pair duplication in the 5' untranslated region, c.-61_-51dup. This change has been previously described in an individual with a single renal cyst and his apparently asymptomatic daughter, both of whom did not fulfill clinical diagnostic criteria of VHL-related disorder (PMID: 30006056). Western blotting and VHL transcript analysis showed milder reduction of VHL gene expression. This sequence change has been described in the gnomAD with a low population frequency of 0.0096% (dbSNP rs529928317). The functional significance of this sequence change is not clearly established at present and its contribution to this patient's disease phenotype cannot definitively be determined. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 10, 2014 | The c.-61_-51dup variant in VHL has previously been identified by our laboratory in 1 individual with VHL. Data from large population studies is insufficient to assess the frequency of this variant. This variant is located in the 5' untrans lated region (UTR) and variants in regulatory regions could have an effect on tr anscriptional or translational efficiency. Studies have shown that sequence alte rations in this region may alter VHL transcription (Zatyka 2002) and our laborat ory has identified a 5' UTR deletion variant in VHL overlapping with this region that segregated with disease in multiple affected individuals (LMM unpublished data). However, in the absence of additional information, further data is needed to fully assess the clinical significance of this variant. - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2019 | This variant is associated with the following publications: (PMID: 30006056, 29790589) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | VHL: BS1 - |
VHL-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 18, 2024 | The VHL c.-61_-51dup11 variant is located in the 5' untranslated region. This variant has been reported in individuals with erythrocytosis (Table 2, Oliveira et al. 2018. PubMed ID: 29790589) and an individual with suspected Von Hippel-Lindau disease (Albanyan et al. 2018. PubMed ID: 30006056). RT-QPCR analysis revealed a modest reduction in RNA (61%) and protein (77%) expression in patient-derived fibroblasts compared to a healthy control (Albanyan et al. 2018. PubMed ID: 30006056). This variant is reported in 3 of ~31,000 alleles in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/517152/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Chuvash polycythemia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Apr 04, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 27, 2021 | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2023 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at