rs13447633
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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.969A>Gā(p.Pro323=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 1,613,250 control chromosomes in the GnomAD database, including 2 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 0.0024 ( 2 hom., cov: 32)
Exomes š: 0.00022 ( 0 hom. )
Consequence
MRE11
NM_005591.4 synonymous
NM_005591.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.593
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=-0.48).
BP6
Variant 11-94470519-T-C is Benign according to our data. Variant chr11-94470519-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 182551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.593 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00244 (371/152234) while in subpopulation AFR AF= 0.0084 (349/41560). AF 95% confidence interval is 0.00767. There are 2 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 371 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.969A>G | p.Pro323= | synonymous_variant | 9/20 | ENST00000323929.8 | NP_005582.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.969A>G | p.Pro323= | synonymous_variant | 9/20 | 1 | NM_005591.4 | ENSP00000325863 | P3 | |
MRE11 | ENST00000323977.7 | c.969A>G | p.Pro323= | synonymous_variant | 9/19 | 1 | ENSP00000326094 | |||
MRE11 | ENST00000407439.7 | c.978A>G | p.Pro326= | synonymous_variant | 9/20 | 2 | ENSP00000385614 | |||
MRE11 | ENST00000393241.8 | c.969A>G | p.Pro323= | synonymous_variant | 9/20 | 5 | ENSP00000376933 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00243 AC: 370AN: 152116Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000689 AC: 173AN: 251124Hom.: 1 AF XY: 0.000464 AC XY: 63AN XY: 135734
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GnomAD4 exome AF: 0.000220 AC: 321AN: 1461016Hom.: 0 Cov.: 31 AF XY: 0.000182 AC XY: 132AN XY: 726816
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GnomAD4 genome AF: 0.00244 AC: 371AN: 152234Hom.: 2 Cov.: 32 AF XY: 0.00245 AC XY: 182AN XY: 74426
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 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) | Mar 06, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 22, 2018 | Variant summary: MRE11A c.969A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00088 in 276836 control chromosomes, predominantly at a frequency of 0.0094 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 150-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.969A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 09, 2022 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 25, 2017 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 02, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 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. - |
Ataxia-telangiectasia-like disorder 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 27, 2016 | - - |
Ataxia-telangiectasia-like disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
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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