rs1131690889
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000321.3(RB1):c.1251_1252del(p.Arg418SerfsTer9) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K417K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
RB1
NM_000321.3 frameshift
NM_000321.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.34
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-48376950-GAA-G is Pathogenic according to our data. Variant chr13-48376950-GAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 428712.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.1251_1252del | p.Arg418SerfsTer9 | frameshift_variant | 13/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.41-2712_41-2711del | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.1251_1252del | p.Arg418SerfsTer9 | frameshift_variant | 13/27 | ||
RB1 | NM_001407166.1 | c.1251_1252del | p.Arg418SerfsTer9 | frameshift_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1251_1252del | p.Arg418SerfsTer9 | frameshift_variant | 13/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1251_1252del | p.Arg418SerfsTer9 | frameshift_variant | 13/27 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2015 | The c.1251_1252delAA pathogenic mutation, located in coding exon 13 of the RB1 gene, results from a deletion of two nucleotides between positions 1251 and 1252, causing a translational frameshift with a predicted alternate stop codon. This mutation was previously identified in one individual diagnosed with bilateral retinoblastoma at age 3 months (Abouzeid H et al. Mol. Vis. 2007;13:1740-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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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