13-48349023-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000321.3(RB1):c.607G>A(p.Gly203Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G203E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense, splice_region
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.607G>A | p.Gly203Arg | missense_variant, splice_region_variant | 6/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.607G>A | p.Gly203Arg | missense_variant, splice_region_variant | 6/27 | ||
RB1 | NM_001407166.1 | c.607G>A | p.Gly203Arg | missense_variant, splice_region_variant | 6/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.607G>A | p.Gly203Arg | missense_variant, splice_region_variant | 6/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.138-10994G>A | intron_variant, NMD_transcript_variant | 1 | |||||
RB1 | ENST00000650461.1 | c.607G>A | p.Gly203Arg | missense_variant, splice_region_variant | 6/27 | ||||
RB1 | ENST00000525036.1 | n.769G>A | splice_region_variant, non_coding_transcript_exon_variant | 6/7 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1442198Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 717528
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2022 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. ClinVar contains an entry for this variant (Variation ID: 1466305). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the RB1 protein (p.Gly203Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.