rs1555286503
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000321.3(RB1):c.1333-2A>G variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000321.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1333-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 26 | ENST00000267163.6 | NP_000312.2 | ||
RB1 | NM_001407165.1 | c.1333-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 26 | NP_001394094.1 | |||
RB1 | NM_001407166.1 | c.1333-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 16 | NP_001394095.1 | |||
LOC112268118 | XR_002957522.2 | n.40+243T>C | intron_variant | Intron 1 of 2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1333-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 26 | 1 | NM_000321.3 | ENSP00000267163.4 | |||
RB1 | ENST00000650461.1 | c.1333-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 26 | ENSP00000497193.1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:2
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Loss-of-function variants in RB1 are known to be pathogenic. This particular variant has been reported in several individuals affected with retinoblastoma in the literature (PMID: 12541220) and in the Leiden Open-source Variation Database (PMID: 21520333). This variant is also known as 1471-2A>G in the literature. For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 13 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at