rs13447632
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_005591.4(MRE11):āc.771A>Gā(p.Glu257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,612,938 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0028 ( 2 hom., cov: 32)
Exomes š: 0.00035 ( 2 hom. )
Consequence
MRE11
NM_005591.4 synonymous
NM_005591.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.288
Genes affected
MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
?
Variant 11-94471648-T-C is Benign according to our data. Variant chr11-94471648-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 182548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-94471648-T-C is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.288 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00281 (427/152156) while in subpopulation AFR AF= 0.00938 (390/41556). AF 95% confidence interval is 0.00862. There are 2 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 427 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.771A>G | p.Glu257= | synonymous_variant | 8/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.771A>G | p.Glu257= | synonymous_variant | 8/20 | 1 | NM_005591.4 | P3 | |
MRE11 | ENST00000323977.7 | c.771A>G | p.Glu257= | synonymous_variant | 8/19 | 1 | |||
MRE11 | ENST00000407439.7 | c.780A>G | p.Glu260= | synonymous_variant | 8/20 | 2 | |||
MRE11 | ENST00000393241.8 | c.771A>G | p.Glu257= | synonymous_variant | 8/20 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00280 AC: 426AN: 152038Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000789 AC: 198AN: 250944Hom.: 1 AF XY: 0.000619 AC XY: 84AN XY: 135616
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GnomAD4 exome AF: 0.000353 AC: 515AN: 1460782Hom.: 2 Cov.: 31 AF XY: 0.000314 AC XY: 228AN XY: 726686
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GnomAD4 genome ? AF: 0.00281 AC: 427AN: 152156Hom.: 2 Cov.: 32 AF XY: 0.00288 AC XY: 214AN XY: 74396
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 17, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 18, 2015 | - - |
Ataxia-telangiectasia-like disorder 1 Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2014 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 08, 2021 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2017 | Variant summary: The MRE11A c.771A>G (p.Glu257Glu) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 281/276646 (2 homozygotes) control chromosomes at a frequency of 0.0010157, which is approximately 16 times the estimated maximal expected allele frequency of a pathogenic MRE11A variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Ataxia-telangiectasia-like disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
MRE11-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 10, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at