13-48303971-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_000321.3(RB1):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,503,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.59C>T | p.Pro20Leu | missense_variant | 1/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.59C>T | p.Pro20Leu | missense_variant | 1/27 | ||
RB1 | NM_001407166.1 | c.59C>T | p.Pro20Leu | missense_variant | 1/17 | ||
RB1 | NM_001407167.1 | c.59C>T | p.Pro20Leu | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.59C>T | p.Pro20Leu | missense_variant | 1/27 | 1 | NM_000321.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 151970Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000128 AC: 13AN: 101296Hom.: 0 AF XY: 0.000123 AC XY: 7AN XY: 56758
GnomAD4 exome AF: 0.000146 AC: 198AN: 1351810Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 93AN XY: 666756
GnomAD4 genome AF: 0.000118 AC: 18AN: 151970Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74234
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces proline with leucine at codon 20 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with retinoblastoma (PMID: 12541220, 14722923, 16343894, 29261756), but also in unaffected individuals (PMID: 16343894, 24728327, 29261756). This variant has been identified in 16/132530 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
not specified Uncertain:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 09, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 18, 2021 | - - |
RB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 31, 2023 | The RB1 c.59C>T variant is predicted to result in the amino acid substitution p.Pro20Leu. This variant was reported in an individual with retinoblastoma (Parma et al. 2017. PubMed ID: 29261756, described as g.2118C>T), but was also found in the patient's asymptomatic mother and has been reported in a healthy ancestrally diverse cohort (Bodian et al. 2014. PubMed ID: 24728327, supplementary data). This variant was also described as a variant of uncertain significance in cohort of individuals with breast cancer (Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/135115/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at