chr13-48453067-T-C
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000321.3(RB1):c.1770T>C(p.Cys590=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,613,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00046 ( 1 hom. )
Consequence
RB1
NM_000321.3 synonymous
NM_000321.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.295
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
?
Variant 13-48453067-T-C is Benign according to our data. Variant chr13-48453067-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 237662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.295 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000598 (91/152288) while in subpopulation AMR AF= 0.00294 (45/15292). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 91 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1770T>C | p.Cys590= | synonymous_variant | 18/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1770T>C | p.Cys590= | synonymous_variant | 18/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1770T>C | p.Cys590= | synonymous_variant | 18/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1770T>C | p.Cys590= | synonymous_variant | 18/27 | ||||
RB1 | ENST00000643064.1 | c.194+71624T>C | intron_variant | ||||||
RB1 | ENST00000480491.1 | n.469T>C | non_coding_transcript_exon_variant | 2/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000598 AC: 91AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000713 AC: 179AN: 250938Hom.: 0 AF XY: 0.000597 AC XY: 81AN XY: 135686
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GnomAD4 exome AF: 0.000461 AC: 673AN: 1460932Hom.: 1 Cov.: 31 AF XY: 0.000465 AC XY: 338AN XY: 726792
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinoblastoma Benign:3
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 15, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2017 | 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | RB1: BP4, BP7, BS1 - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at