chr13-48380164-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000321.3(RB1):c.1422-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1422-1G>T | splice_acceptor_variant, intron_variant | Intron 15 of 26 | ENST00000267163.6 | NP_000312.2 | ||
RB1 | NM_001407165.1 | c.1422-1G>T | splice_acceptor_variant, intron_variant | Intron 15 of 26 | NP_001394094.1 | |||
RB1 | NM_001407166.1 | c.1422-1G>T | splice_acceptor_variant, intron_variant | Intron 15 of 16 | NP_001394095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1422-1G>T | splice_acceptor_variant, intron_variant | Intron 15 of 26 | 1 | NM_000321.3 | ENSP00000267163.4 | |||
RB1 | ENST00000650461.1 | c.1422-1G>T | splice_acceptor_variant, intron_variant | Intron 15 of 26 | ENSP00000497193.1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1AN: 144816Hom.: 0 Cov.: 30 FAILED QC
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000636 AC: 9AN: 1415680Hom.: 0 Cov.: 31 AF XY: 0.00000711 AC XY: 5AN XY: 702904
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000691 AC: 1AN: 144816Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 69966
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.1422-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 16 of the RB1 gene. This alteration was seen in a one-year-old patient with bilateral retinoblastoma (Ottaviani D et al. Ophthalmic Genet., 2013 Dec;34:189-98). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at