11-108279501-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000051.4(ATM):c.3295G>T(p.Asp1099Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,609,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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.3295G>T | p.Asp1099Tyr | missense_variant | Exon 23 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1457008Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 724648
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
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This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Tyr). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 421832). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.D1099Y variant (also known as c.3295G>T), located in coding exon 22 of the ATM gene, results from a G to T substitution at nucleotide position 3295. The aspartic acid at codon 1099 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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. -
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at