13-48380232-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000321.3(RB1):c.1489A>G(p.Thr497Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000025 in 1,596,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1489A>G | p.Thr497Ala | missense_variant | Exon 16 of 27 | ENST00000267163.6 | NP_000312.2 | |
RB1 | NM_001407165.1 | c.1489A>G | p.Thr497Ala | missense_variant | Exon 16 of 27 | NP_001394094.1 | ||
RB1 | NM_001407166.1 | c.1489A>G | p.Thr497Ala | missense_variant | Exon 16 of 17 | NP_001394095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1489A>G | p.Thr497Ala | missense_variant | Exon 16 of 27 | 1 | NM_000321.3 | ENSP00000267163.4 | ||
RB1 | ENST00000650461.1 | c.1489A>G | p.Thr497Ala | missense_variant | Exon 16 of 27 | ENSP00000497193.1 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151686Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000808 AC: 2AN: 247442Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133924
GnomAD4 exome AF: 0.00000208 AC: 3AN: 1445302Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2AN XY: 719766
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151686Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74016
ClinVar
Submissions by phenotype
not specified Uncertain:1
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Retinoblastoma Uncertain:1
This sequence change replaces threonine with alanine at codon 497 of the RB1 protein (p.Thr497Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs776531398, ExAC 0.002%) but has not been reported in the literature in individuals with a RB1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at