rs863224734
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_005591.4(MRE11):c.1225+10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
MRE11
NM_005591.4 intron
NM_005591.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.42
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 Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
?
Variant 11-94464103-A-C is Benign according to our data. Variant chr11-94464103-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216606.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
?
High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1225+10T>G | intron_variant | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1225+10T>G | intron_variant | 1 | NM_005591.4 | P3 | |||
MRE11 | ENST00000323977.7 | c.1225+10T>G | intron_variant | 1 | |||||
MRE11 | ENST00000393241.8 | c.1225+10T>G | intron_variant | 5 | A1 | ||||
MRE11 | ENST00000407439.7 | c.1234+10T>G | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152230Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1459868Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726316
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Ataxia-telangiectasia-like disorder 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2021 | The MRE11 c.1225+10T>G variant (rs863224734), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 216606). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice, although RNA studies would be required to confirm an effect on splicing. Given the lack of clinical and functional data, the significance of the c.1225+10T>G variant is uncertain at this time. - |
Ataxia-telangiectasia-like disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at