rs61749249
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005591.4(MRE11):c.1475C>T(p.Ala492Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. A492D) has been classified as Likely benign.
Frequency
Consequence
NM_005591.4 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1475C>T | p.Ala492Val | missense_variant | Exon 13 of 20 | ENST00000323929.8 | NP_005582.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1475C>T | p.Ala492Val | missense_variant | Exon 13 of 20 | 1 | NM_005591.4 | ENSP00000325863.4 | ||
MRE11 | ENST00000323977.7 | c.1475C>T | p.Ala492Val | missense_variant | Exon 13 of 19 | 1 | ENSP00000326094.3 | |||
MRE11 | ENST00000407439.7 | c.1484C>T | p.Ala495Val | missense_variant | Exon 13 of 20 | 2 | ENSP00000385614.3 | |||
MRE11 | ENST00000393241.8 | c.1475C>T | p.Ala492Val | missense_variant | Exon 13 of 20 | 5 | ENSP00000376933.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251386Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461686Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727152
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
ClinVar
Submissions by phenotype
Ataxia-telangiectasia-like disorder 1 Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.A492V variant (also known as c.1475C>T), located in coding exon 12 of the MRE11A gene, results from a C to T substitution at nucleotide position 1475. The alanine at codon 492 is replaced by valine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. 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 p.A492V remains unclear. -
Ataxia-telangiectasia-like disorder Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 492 of the MRE11 protein (p.Ala492Val). This variant is present in population databases (rs61749249, gnomAD 0.003%). 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: 231931). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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