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
Consequence
NM_000551.4 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
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 AF: 0.000282 AC: 43AN: 152230Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.000452 AC: 618AN: 1366002Hom.: 7 Cov.: 29 AF XY: 0.000565 AC XY: 381AN XY: 674038
GnomAD4 genome AF: 0.000276 AC: 42AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74506
ClinVar
Submissions by phenotype
not specified Uncertain:2
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deletion variant in VHL overlapping with this region that segregated with disease in multiple affected individuals (LMM unpublished data).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. -
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. -
not provided Benign:2
This variant is associated with the following publications: (PMID: 30006056, 29790589) -
VHL: BS1 -
VHL-related disorder Uncertain:1
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
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Hereditary cancer-predisposing syndrome Uncertain:1
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Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at