rs201285819
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_Very_StrongBP7BS2_Supporting
The NM_000321.3(RB1):c.1356G>A(p.Leu452=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
RB1
NM_000321.3 synonymous
NM_000321.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.283
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 -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
?
Variant 13-48379617-G-A is Benign according to our data. Variant chr13-48379617-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1081187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.283 with no splicing effect.
BS2
?
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1356G>A | p.Leu452= | synonymous_variant | 14/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.40+218C>T | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.1356G>A | p.Leu452= | synonymous_variant | 14/27 | ||
RB1 | NM_001407166.1 | c.1356G>A | p.Leu452= | synonymous_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1356G>A | p.Leu452= | synonymous_variant | 14/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1356G>A | p.Leu452= | synonymous_variant | 14/27 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249876Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135344
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460410Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 726448
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74236
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinoblastoma Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 03, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2023 | 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
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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