11-108235717-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000051.4(ATM):c.379A>G(p.Thr127Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,459,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.379A>G | p.Thr127Ala | missense_variant | Exon 5 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1459952Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726476
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces threonine with alanine at codon 127 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
The p.T127A variant (also known as c.379A>G), located in coding exon 4 of the ATM gene, results from an A to G substitution at nucleotide position 379. The threonine at codon 127 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam. Cancer 2017 07;16:319-328). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Ataxia-telangiectasia syndrome Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 127 of the ATM protein (p.Thr127Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 27878467). ClinVar contains an entry for this variant (Variation ID: 141432). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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