rs1208736713
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000321.3(RB1):c.905C>A(p.Ser302Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000352 in 1,418,480 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. S302F) has been classified 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.905C>A | p.Ser302Tyr | missense_variant | 9/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.161G>T | non_coding_transcript_exon_variant | 3/3 | |||
RB1 | NM_001407165.1 | c.905C>A | p.Ser302Tyr | missense_variant | 9/27 | ||
RB1 | NM_001407166.1 | c.905C>A | p.Ser302Tyr | missense_variant | 9/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.905C>A | p.Ser302Tyr | missense_variant | 9/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.905C>A | p.Ser302Tyr | missense_variant | 9/27 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000352 AC: 5AN: 1418480Hom.: 0 Cov.: 30 AF XY: 0.00000427 AC XY: 3AN XY: 702188
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 26, 2023 | This missense variant replaces serine with tyrosine at codon 302 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 not been identified 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 302 of the RB1 protein (p.Ser302Tyr). This variant is not present in population databases (gnomAD no frequency). 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: 458187). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2024 | The p.S302Y variant (also known as c.905C>A), located in coding exon 9 of the RB1 gene, results from a C to A substitution at nucleotide position 905. The serine at codon 302 is replaced by tyrosine, an amino acid with dissimilar properties. This variant has been detected in multiple individuals with no reported features of RB1-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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