rs779250359
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_005591.4(MRE11):c.1563G>A(p.Glu521=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000103 in 1,460,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005591.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRE11 | NM_005591.4 | c.1563G>A | p.Glu521= | splice_region_variant, synonymous_variant | 14/20 | ENST00000323929.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRE11 | ENST00000323929.8 | c.1563G>A | p.Glu521= | splice_region_variant, synonymous_variant | 14/20 | 1 | NM_005591.4 | P3 | |
MRE11 | ENST00000323977.7 | c.1563G>A | p.Glu521= | splice_region_variant, synonymous_variant | 14/19 | 1 | |||
MRE11 | ENST00000407439.7 | c.1572G>A | p.Glu524= | splice_region_variant, synonymous_variant | 14/20 | 2 | |||
MRE11 | ENST00000393241.8 | c.1563G>A | p.Glu521= | splice_region_variant, synonymous_variant | 14/20 | 5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250688Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135522
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460980Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 726840
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 20, 2019 | The c.1563G>A variant (also known as p.E521E), located in coding exon 13 of the MRE11A gene, results from a G to A substitution at nucleotide position 1563. This nucleotide substitution does not change the amino acid at codon 521. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. 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 | Aug 15, 2022 | This sequence change affects codon 521 of the MRE11 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MRE11 protein. This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is present in population databases (rs779250359, gnomAD 0.01%). 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: 240185). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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