rs181988132
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000321.3(RB1):c.1174G>A(p.Ala392Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,598,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1174G>A | p.Ala392Thr | missense_variant | 12/27 | ENST00000267163.6 | NP_000312.2 | |
RB1 | NM_001407165.1 | c.1174G>A | p.Ala392Thr | missense_variant | 12/27 | NP_001394094.1 | ||
RB1 | NM_001407166.1 | c.1174G>A | p.Ala392Thr | missense_variant | 12/17 | NP_001394095.1 | ||
LOC112268118 | XR_002957522.2 | n.121+709C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1174G>A | p.Ala392Thr | missense_variant | 12/27 | 1 | NM_000321.3 | ENSP00000267163.4 | ||
RB1 | ENST00000650461.1 | c.1174G>A | p.Ala392Thr | missense_variant | 12/27 | ENSP00000497193.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151992Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250622Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135474
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1445960Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 720224
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 10, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 392 of the RB1 protein (p.Ala392Thr). This variant is present in population databases (rs181988132, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 458119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces alanine with threonine at codon 392 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/250622 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. - |
Malignant tumor of urinary bladder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 28, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2024 | The p.A392T variant (also known as c.1174G>A), located in coding exon 12 of the RB1 gene, results from a G to A substitution at nucleotide position 1174. The alanine at codon 392 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 27, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at