rs587776779
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000321.3(RB1):c.2520+1del variant causes a frameshift, splice region change. 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
RB1
NM_000321.3 frameshift, splice_region
NM_000321.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.97
Genes affected
RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 13-48473387-CG-C is Pathogenic according to our data. Variant chr13-48473387-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 13069.Status of the report is criteria_provided_single_submitter, 1 stars.
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
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 exome
Data not reliable, filtered out with message: AC0
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1410152
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28
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0
AN XY:
704282
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinoblastoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 21, 1989 | - - |
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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at