13-48381295-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000321.3(RB1):c.1547G>C(p.Trp516Ser) 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. W516R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1547G>C | p.Trp516Ser | missense_variant | 17/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1547G>C | p.Trp516Ser | missense_variant | 17/27 | ||
RB1 | NM_001407166.1 | c.1547G>C | p.Trp516Ser | missense_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1547G>C | p.Trp516Ser | missense_variant | 17/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1547G>C | p.Trp516Ser | missense_variant | 17/27 | ||||
RB1 | ENST00000643064.1 | c.47G>C | p.Trp16Ser | missense_variant | 1/2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2023 | This variant is not present in population databases (gnomAD no frequency). 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. 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 expected to disrupt RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 458131). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 516 of the RB1 protein (p.Trp516Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at