rs1060503079
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000321.3(RB1):c.1328C>A(p.Ser443Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
RB1
NM_000321.3 stop_gained
NM_000321.3 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 0.783
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 18 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 13-48377030-C-A is Pathogenic according to our data. Variant chr13-48377030-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 410927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48377030-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1328C>A | p.Ser443Ter | stop_gained | 13/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.41-2790G>T | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.1328C>A | p.Ser443Ter | stop_gained | 13/27 | ||
RB1 | NM_001407166.1 | c.1328C>A | p.Ser443Ter | stop_gained | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1328C>A | p.Ser443Ter | stop_gained | 13/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1328C>A | p.Ser443Ter | stop_gained | 13/27 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
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, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2016 | Loss-of-function variants in RB1 are known to be pathogenic. This particular variant has been reported in the literature in an individual with retinoblastoma (PMID: 12541220). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal at codon 443 (p.Ser443*) of the RB1 gene. It is expected to result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 30, 2014 | The p.S443* pathogenic mutation (also known as c.1328C>A) located in coding exon 13 of the RB1 gene, results from a C to A substitution at nucleotide position 1328. This changes the amino acid from a serine to a stop codon within coding exon 13. This alteration was previously identified in an individual with bilateral retinoblastoma (Richter S, Am. J. Hum. Genet. 2003 Feb; 72(2):253-69). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at