rs190689977
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000321.3(RB1):c.1159A>G(p.Met387Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M387L) has been classified 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1159A>G | p.Met387Val | missense_variant | 12/27 | ENST00000267163.6 | |
LOC112268118 | XR_002957522.2 | n.121+724T>C | intron_variant, non_coding_transcript_variant | ||||
RB1 | NM_001407165.1 | c.1159A>G | p.Met387Val | missense_variant | 12/27 | ||
RB1 | NM_001407166.1 | c.1159A>G | p.Met387Val | missense_variant | 12/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1159A>G | p.Met387Val | missense_variant | 12/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1159A>G | p.Met387Val | missense_variant | 12/27 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 01, 2022 | 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 387 of the RB1 protein (p.Met387Val). This variant is not present in population databases (gnomAD no frequency). 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: 458117). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2022 | The p.M387V variant (also known as c.1159A>G), located in coding exon 12 of the RB1 gene, results from an A to G substitution at nucleotide position 1159. The methionine at codon 387 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. 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