rs769425649
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000321.3(RB1):c.1364G>A(p.Arg455Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000807 in 1,611,846 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 Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1364G>A | p.Arg455Gln | missense_variant | Exon 14 of 27 | ENST00000267163.6 | NP_000312.2 | |
RB1 | NM_001407165.1 | c.1364G>A | p.Arg455Gln | missense_variant | Exon 14 of 27 | NP_001394094.1 | ||
RB1 | NM_001407166.1 | c.1364G>A | p.Arg455Gln | missense_variant | Exon 14 of 17 | NP_001394095.1 | ||
LOC112268118 | XR_002957522.2 | n.40+210C>T | intron_variant | Intron 1 of 2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1364G>A | p.Arg455Gln | missense_variant | Exon 14 of 27 | 1 | NM_000321.3 | ENSP00000267163.4 | ||
RB1 | ENST00000650461.1 | c.1364G>A | p.Arg455Gln | missense_variant | Exon 14 of 27 | ENSP00000497193.1 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151526Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249800Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135264
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460320Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 726410
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151526Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 73950
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:2
This missense variant replaces arginine with glutamine at codon 455 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has been identified in 1/249800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 455 of the RB1 protein (p.Arg455Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 577156). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. 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. -
Malignant tumor of urinary bladder Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.R455Q variant (also known as c.1364G>A), located in coding exon 14 of the RB1 gene, results from a G to A substitution at nucleotide position 1364. The arginine at codon 455 is replaced by glutamine, 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