chr13-48347863-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBP6BS2
The NM_000321.3(RB1):c.539C>T(p.Ser180Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,582,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S180W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000321.3 missense, splice_region
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.539C>T | p.Ser180Leu | missense_variant, splice_region_variant | 5/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.539C>T | p.Ser180Leu | missense_variant, splice_region_variant | 5/27 | ||
RB1 | NM_001407166.1 | c.539C>T | p.Ser180Leu | missense_variant, splice_region_variant | 5/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.539C>T | p.Ser180Leu | missense_variant, splice_region_variant | 5/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.138-12154C>T | intron_variant, NMD_transcript_variant | 1 | |||||
RB1 | ENST00000650461.1 | c.539C>T | p.Ser180Leu | missense_variant, splice_region_variant | 5/27 | ||||
RB1 | ENST00000525036.1 | n.701C>T | splice_region_variant, non_coding_transcript_exon_variant | 5/7 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151576Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000403 AC: 10AN: 248194Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134314
GnomAD4 exome AF: 0.0000678 AC: 97AN: 1430564Hom.: 0 Cov.: 28 AF XY: 0.0000589 AC XY: 42AN XY: 713286
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151576Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73982
ClinVar
Submissions by phenotype
Retinoblastoma Benign:3
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine | May 20, 2024 | Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:1, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:BP4, BP6 - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
RB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 20, 2023 | The RB1 c.539C>T variant is predicted to result in the amino acid substitution p.Ser180Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-48921999-C-T). In ClinVar, this variant is classified as likely benign and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/527940/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | RB1: BP4 - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2019 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at