13-48463758-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000321.3(RB1):c.2134T>A(p.Cys712Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C712R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.2134T>A | p.Cys712Ser | missense_variant | 21/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.2134T>A | p.Cys712Ser | missense_variant | 21/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.2134T>A | p.Cys712Ser | missense_variant | 21/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.2134T>A | p.Cys712Ser | missense_variant | 21/27 | ||||
RB1 | ENST00000643064.1 | c.194+82315T>A | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 11, 2021 | 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. This variant disrupts the p.Cys712 amino acid residue in RB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9671401, 10671068, 11668642, 22084214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RB1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 712 of the RB1 protein (p.Cys712Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.