rs587776779
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000321.3(RB1):c.2520+1del variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G840G) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000321.3 frameshift, splice_region
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.2520+1del | frameshift_variant, splice_region_variant | 24/27 | ENST00000267163.6 | ||
RB1 | NM_001407165.1 | c.2520+1del | frameshift_variant, splice_region_variant | 24/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.2520+1del | frameshift_variant, splice_region_variant | 24/27 | 1 | NM_000321.3 | P1 | ||
RB1 | ENST00000650461.1 | c.2520+1del | frameshift_variant, splice_region_variant | 24/27 | |||||
RB1 | ENST00000643064.1 | c.194+91948del | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1410152Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 704282
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 21, 1989 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine | May 20, 2024 | Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:1, TOTAL CASES:2, PEDIGREES:2. ACMG Codes Applied:PVS1, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2022 | The c.2520+1delG intronic pathogenic mutation, located in intron 24 of the RB1 gene, results from a deletion of one nucleotide within intron 24 of the RB1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with RB1-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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