13-48349024-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000321.3(RB1):c.607+1G>C variant causes a splice donor, intron change. 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_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.607+1G>C | splice_donor_variant, intron_variant | Intron 6 of 26 | ENST00000267163.6 | NP_000312.2 | ||
RB1 | NM_001407165.1 | c.607+1G>C | splice_donor_variant, intron_variant | Intron 6 of 26 | NP_001394094.1 | |||
RB1 | NM_001407166.1 | c.607+1G>C | splice_donor_variant, intron_variant | Intron 6 of 16 | NP_001394095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.607+1G>C | splice_donor_variant, intron_variant | Intron 6 of 26 | 1 | NM_000321.3 | ENSP00000267163.4 | |||
RB1 | ENST00000467505.5 | n.138-10993G>C | intron_variant | Intron 1 of 2 | 1 | ENSP00000434702.1 | ||||
RB1 | ENST00000650461.1 | c.607+1G>C | splice_donor_variant, intron_variant | Intron 6 of 26 | ENSP00000497193.1 | |||||
RB1 | ENST00000525036.1 | n.769+1G>C | splice_donor_variant, intron_variant | Intron 6 of 6 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:2
Case and Pedigree Information: BILATERAL CASES:5, UNILATERAL CASES:0, TOTAL CASES:5, PEDIGREES:4. ACMG Codes Applied:PVS1, PM2, PS4SUP -
This sequence change affects a donor splice site in intron 6 of the RB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 8651278, 12016586, 26925970; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1459669). Studies have shown that disruption of this splice site results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18000883). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.607+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 6 of the RB1 gene. This alteration has been detected in several individuals with bilateral retinoblastoma in early childhood (Ambry internal data; Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58(5):940-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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
Publications
No publications associated with this variant yet.