rs121913298
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000321.3(RB1):c.596T>A(p.Leu199Ter) variant causes a stop gained change. 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 (★). Synonymous variant affecting the same amino acid position (i.e. L199L) has been classified as Likely benign. 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
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.48
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 13-48349012-T-A is Pathogenic according to our data. Variant chr13-48349012-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 376329.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-48349012-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.596T>A | p.Leu199Ter | stop_gained | 6/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.596T>A | p.Leu199Ter | stop_gained | 6/27 | ||
RB1 | NM_001407166.1 | c.596T>A | p.Leu199Ter | stop_gained | 6/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.596T>A | p.Leu199Ter | stop_gained | 6/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.138-11005T>A | intron_variant, NMD_transcript_variant | 1 | |||||
RB1 | ENST00000650461.1 | c.596T>A | p.Leu199Ter | stop_gained | 6/27 | ||||
RB1 | ENST00000525036.1 | n.758T>A | non_coding_transcript_exon_variant | 6/7 | 3 |
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, single submitter
LINK: link
Submissions by phenotype
Retinoblastoma Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 376329). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 25712084). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu199*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). - |
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
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