chr13-48473361-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP6BS2
The NM_000321.3(RB1):c.2491A>G(p.Ile831Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000152 in 1,574,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I831L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.2491A>G | p.Ile831Val | missense_variant, splice_region_variant | 24/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.2491A>G | p.Ile831Val | missense_variant, splice_region_variant | 24/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.2491A>G | p.Ile831Val | missense_variant, splice_region_variant | 24/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.2491A>G | p.Ile831Val | missense_variant, splice_region_variant | 24/27 | ||||
RB1 | ENST00000643064.1 | c.194+91918A>G | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250614Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135578
GnomAD4 exome AF: 0.0000155 AC: 22AN: 1422206Hom.: 0 Cov.: 28 AF XY: 0.0000197 AC XY: 14AN XY: 709798
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 07, 2023 | This missense variant replaces isoleucine with valine at codon 831 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 not been reported in individuals affected with RB1-related disorders in the literature. This variant has been identified in 5/250614 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 15, 2023 | Variant summary: RB1 c.2491A>G (p.Ile831Val) results in a conservative amino acid change located in the Retinoblastoma-associated protein, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.5e-05 in 1574358 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RB1 causing Retinoblastoma (1.5e-05 vs 4.2e-05), allowing no conclusion about variant significance. c.2491A>G has been reported in the literature in individuals affected with unspecified cancer (deOliveira_2022). This report does not provide unequivocal conclusions about association of the variant with Retinoblastoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at