11-108250835-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):c.1370G>T(p.Arg457Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,613,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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 Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.1370G>T | p.Arg457Leu | missense_variant | Exon 10 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152102Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251396Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135864
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461864Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 727228
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152102Hom.: 1 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3
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This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 457 of the ATM protein (p.Arg457Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 219530). 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. -
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not provided Uncertain:2
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Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual via whole exome sequencing; however, no personal health history was provided (Rodriguez-Flores 2014); This variant is associated with the following publications: (PMID: 24123366, 31422574) -
Hereditary cancer-predisposing syndrome Uncertain:2
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The p.R457L variant (also known as c.1370G>T), located in coding exon 9 of the ATM gene, results from a G to T substitution at nucleotide position 1370. The arginine at codon 457 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Familial cancer of breast Uncertain:2
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This sequence change replaces arginine with leucine at codon 457 of the ATM protein (p.Arg457Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (gnomAD). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 219530). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align- GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at