rs1220347917
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000321.3(RB1):c.552A>C(p.Glu184Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,450,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E184E) has been classified as Likely benign.
Frequency
Consequence
NM_000321.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.552A>C | p.Glu184Asp | missense_variant | 6/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.552A>C | p.Glu184Asp | missense_variant | 6/27 | ||
RB1 | NM_001407166.1 | c.552A>C | p.Glu184Asp | missense_variant | 6/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.552A>C | p.Glu184Asp | missense_variant | 6/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000467505.5 | c.138-11049A>C | intron_variant, NMD_transcript_variant | 1 | |||||
RB1 | ENST00000650461.1 | c.552A>C | p.Glu184Asp | missense_variant | 6/27 | ||||
RB1 | ENST00000525036.1 | n.714A>C | non_coding_transcript_exon_variant | 6/7 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248766Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134778
GnomAD4 exome AF: 0.00000276 AC: 4AN: 1450196Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2AN XY: 721418
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces glutamic acid with aspartic acid at codon 184 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 1/248766 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 527928). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 184 of the RB1 protein (p.Glu184Asp). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2019 | The p.E184D variant (also known as c.552A>C), located in coding exon 6 of the RB1 gene, results from an A to C substitution at nucleotide position 552. The glutamic acid at codon 184 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at