chr11-94464175-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting
The NM_005591.4(MRE11):c.1163G>A(p.Arg388Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. R388P) has been classified as Uncertain significance.
Frequency
Consequence
NM_005591.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1163G>A | p.Arg388Gln | missense_variant | 11/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1163G>A | p.Arg388Gln | missense_variant | 11/20 | 1 | NM_005591.4 | P3 | |
MRE11 | ENST00000323977.7 | c.1163G>A | p.Arg388Gln | missense_variant | 11/19 | 1 | |||
MRE11 | ENST00000407439.7 | c.1172G>A | p.Arg391Gln | missense_variant | 11/20 | 2 | |||
MRE11 | ENST00000393241.8 | c.1163G>A | p.Arg388Gln | missense_variant | 11/20 | 5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251260Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135800
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461618Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727112
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 08, 2019 | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00014 (5/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 08, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2014 | MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.1163G>A at the cDNA level, p.Arg388Gln (R388Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg388Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the MRE11A gene, remain unclear. - |
Ataxia-telangiectasia-like disorder 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 13, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2022 | The p.R388Q variant (also known as c.1163G>A), located in coding exon 10 of the MRE11A gene, results from a G to A substitution at nucleotide position 1163. The arginine at codon 388 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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. - |
Ataxia-telangiectasia-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 388 of the MRE11 protein (p.Arg388Gln). This variant is present in population databases (rs587780134, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MRE11-related conditions. ClinVar contains an entry for this variant (Variation ID: 127969). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at