chr13-48379624-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000321.3(RB1):c.1363C>T(p.Arg455Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,612,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R455R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000321.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1363C>T | p.Arg455Ter | stop_gained | 14/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.40+211G>A | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.1363C>T | p.Arg455Ter | stop_gained | 14/27 | ||
RB1 | NM_001407166.1 | c.1363C>T | p.Arg455Ter | stop_gained | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1363C>T | p.Arg455Ter | stop_gained | 14/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1363C>T | p.Arg455Ter | stop_gained | 14/27 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151656Hom.: 0 Cov.: 30
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460360Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726444
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151656Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74026
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:3
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:10, UNILATERAL CASES:1, TOTAL CASES:11, PEDIGREES:11. ACMG Codes Applied:PVS1, PM2, PS4M - |
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change creates a premature translational stop signal (p.Arg455*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 8651278, 17096365, 20059380, 25928201, 27582626, 28575107). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126837). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 22, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8968104, 24791139, 8178820, 25151137, 17205527, 23532519, 20059380, 10671068, 17960112, 28575107, 27582626, 8651278, 25602518, 22278416, 12541220, 8346255, 14769601, 25525159, 25928201, 24347427, 16269091, 1352398, 17096365, 15605413, 11317357, 15884040, 14722923, 19280657, 25712084, 23981928, 16343894, 22180099, 28803391, 33456302, 24810223, 22219649) - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Dec 21, 2022 | - - |
Malignant tumor of urinary bladder Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2023 | The p.R455* pathogenic mutation (also known as c.1363C>T), located in coding exon 14 of the RB1 gene, results from a C to T substitution at nucleotide position 1363. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration has been identified in multiple individuals with both unilateral and bilateral retinoblastoma (Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58(5):940-9; Saliminejad K et al. J. Genet. 2013 May;92(2):e36-40; He MY et al. Mol. Vis. 2014 Apr; 20:545-52; Amitrano S et al. Eur. J. Hum. Genet. 2015 Nov;23(11): 1523-30); Yousef YA et al. Fam. Cancer. 2018 Apr;17(2):261-268). Additionally, this alteration has been reported in a family where two siblings with bilateral retinoblastoma were both found to be heterozygous, but their mother, who had unilateral retinoblastoma, was determined to be mosaic (Rushlow D et al. Hum. Mutat. 2009 May; 30(5):842-51). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at