3-10142116-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_000551.4(VHL):c.269A>G(p.Asn90Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,640 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N90I) has been classified as Pathogenic.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.269A>G | p.Asn90Ser | missense_variant | Exon 1 of 3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.269A>G | p.Asn90Ser | missense_variant | Exon 1 of 3 | NP_001341652.1 | ||
VHL | NM_198156.3 | c.269A>G | p.Asn90Ser | missense_variant | Exon 1 of 2 | NP_937799.1 | ||
VHL | NR_176335.1 | n.339A>G | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1449640Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 721594
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Uncertain:1
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Chuvash polycythemia Uncertain:1
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Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 90 of the VHL protein (p.Asn90Ser). 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: 41865). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. 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. -
not provided Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.N90S variant (also known as c.269A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 269. The asparagine at codon 90 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at