rs3092895
Positions:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000321.3(RB1):āc.1707A>Gā(p.Leu569=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,612,770 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00055 ( 1 hom., cov: 32)
Exomes š: 0.00054 ( 5 hom. )
Consequence
RB1
NM_000321.3 synonymous
NM_000321.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.779
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=-0.52).
BP6
?
Variant 13-48453004-A-G is Benign according to our data. Variant chr13-48453004-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 312291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48453004-A-G is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.779 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000552 (84/152268) while in subpopulation SAS AF= 0.00166 (8/4824). AF 95% confidence interval is 0.000825. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 84 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1707A>G | p.Leu569= | synonymous_variant | 18/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1707A>G | p.Leu569= | synonymous_variant | 18/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1707A>G | p.Leu569= | synonymous_variant | 18/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1707A>G | p.Leu569= | synonymous_variant | 18/27 | ||||
RB1 | ENST00000643064.1 | c.194+71561A>G | intron_variant | ||||||
RB1 | ENST00000480491.1 | n.406A>G | non_coding_transcript_exon_variant | 2/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000552 AC: 84AN: 152150Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000638 AC: 160AN: 250660Hom.: 0 AF XY: 0.000671 AC XY: 91AN XY: 135542
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GnomAD4 exome AF: 0.000540 AC: 788AN: 1460502Hom.: 5 Cov.: 31 AF XY: 0.000612 AC XY: 445AN XY: 726594
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GnomAD4 genome ? AF: 0.000552 AC: 84AN: 152268Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38AN XY: 74470
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinoblastoma Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 15, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 29, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 13, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2015 | 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 | May 01, 2024 | RB1: BP4, BP7 - |
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