rs147009251
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000051.4(ATM):āc.86A>Cā(p.Lys29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,448 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K29R) has been classified 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.86A>C | p.Lys29Thr | missense_variant | 3/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.86A>C | p.Lys29Thr | missense_variant | 3/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251106Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135838
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461448Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727024
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 29 of the ATM protein (p.Lys29Thr). This variant is present in population databases (rs147009251, gnomAD 0.01%). 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: 246102). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2015 | This variant is denoted ATM c.86A>C at the cDNA level, p.Lys29Thr (K29T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys29Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Lys29Thr occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Lys29Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2023 | The p.K29T variant (also known as c.86A>C), located in coding exon 2 of the ATM gene, results from an A to C substitution at nucleotide position 86. The lysine at codon 29 is replaced by threonine, an amino acid with similar properties. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at