rs876659322
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_005591.4(MRE11):āc.740A>Gā(p.His247Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H247D) has been classified as Uncertain significance.
Frequency
Consequence
NM_005591.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.740A>G | p.His247Arg | missense_variant | 8/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.740A>G | p.His247Arg | missense_variant | 8/20 | 1 | NM_005591.4 | P3 | |
MRE11 | ENST00000323977.7 | c.740A>G | p.His247Arg | missense_variant | 8/19 | 1 | |||
MRE11 | ENST00000407439.7 | c.749A>G | p.His250Arg | missense_variant | 8/20 | 2 | |||
MRE11 | ENST00000393241.8 | c.740A>G | p.His247Arg | missense_variant | 8/20 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460690Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726630
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74278
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2022 | The p.H247R variant (also known as c.740A>G), located in coding exon 7 of the MRE11A gene, results from an A to G substitution at nucleotide position 740. The histidine at codon 247 is replaced by arginine, 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 deleterious 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 | Oct 13, 2022 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 247 of the MRE11 protein (p.His247Arg). This variant is not present in population databases (gnomAD no frequency). 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: 231725). 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 disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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