chr13-48379606-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The ENST00000267163.6(RB1):c.1345G>A(p.Gly449Arg) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G449E) has been classified as Pathogenic.
Frequency
Consequence
ENST00000267163.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1345G>A | p.Gly449Arg | missense_variant | 14/27 | ENST00000267163.6 | NP_000312.2 | |
LOC112268118 | XR_002957522.2 | n.40+229C>T | intron_variant, non_coding_transcript_variant | |||||
RB1 | NM_001407165.1 | c.1345G>A | p.Gly449Arg | missense_variant | 14/27 | NP_001394094.1 | ||
RB1 | NM_001407166.1 | c.1345G>A | p.Gly449Arg | missense_variant | 14/17 | NP_001394095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1345G>A | p.Gly449Arg | missense_variant | 14/27 | 1 | NM_000321.3 | ENSP00000267163 | P1 | |
RB1 | ENST00000650461.1 | c.1345G>A | p.Gly449Arg | missense_variant | 14/27 | ENSP00000497193 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 17, 2020 | For these reasons, this variant has been classified as Pathogenic. 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 been reported to be de novo in individuals affected with bilateral retinoblastoma (PMID: 28193182, Invitae) and has been observed to segregate with retinoblastoma in a family (PMID: 17096365). The variant is also known as g.76442G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 428669). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 449 of the RB1 protein (p.Gly449Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine | May 20, 2024 | Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM1, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 02, 2012 | Co-segregation data for this variant is currently unavailable. This variant has not been detected in conjunction with a pathogenic mutation to date. Allele frequency data in population-based cohorts is not currently available. This amino acid position is completely conserved on sequence alignment.This alteration is predicted to be deleterious with a score of 0.010 (conservation: 1.79) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at