rs779269083
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_005591.4(MRE11):c.229G>T(p.Glu77Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,610 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MRE11
NM_005591.4 stop_gained
NM_005591.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.99
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 Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-94486009-C-A is Pathogenic according to our data. Variant chr11-94486009-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224574.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.229G>T | p.Glu77Ter | stop_gained | 4/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.229G>T | p.Glu77Ter | stop_gained | 4/20 | 1 | NM_005591.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461610Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727112
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2020 | The p.E77* pathogenic mutation (also known as c.229G>T), located in coding exon 3 of the MRE11A gene, results from a G to T substitution at nucleotide position 229. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Ataxia-telangiectasia-like disorder 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2023 | - - |
Ataxia-telangiectasia-like disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with endometrium cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224574). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu77*) in the MRE11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
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