chr13-48367521-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000321.3(RB1):c.967G>T(p.Glu323Ter) 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 (★★). 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: 5.56
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 19 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;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 13-48367521-G-T is Pathogenic according to our data. Variant chr13-48367521-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 410924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48367521-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.967G>T | p.Glu323Ter | stop_gained | 10/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.122-2545C>A | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.967G>T | p.Glu323Ter | stop_gained | 10/27 | ||
RB1 | NM_001407166.1 | c.967G>T | p.Glu323Ter | stop_gained | 10/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.967G>T | p.Glu323Ter | stop_gained | 10/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.967G>T | p.Glu323Ter | stop_gained | 10/27 |
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:2
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:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2021 | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 410924). This premature translational stop signal has been observed in individuals with retinoblastoma (PMID: 12541220, 24791139, 25754945, 26396485). This sequence change creates a premature translational stop signal (p.Glu323*) 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). - |
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
DS_AL_spliceai
Position offset: -27
Find out detailed SpliceAI scores and Pangolin per-transcript scores at