11-108315863-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000051.4(ATM):c.6047A>T(p.Asp2016Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2016G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6047A>T | p.Asp2016Val | missense_variant | 41/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6047A>T | p.Asp2016Val | missense_variant | 41/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461290Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727022
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2021 | This variant disrupts the p.Asp2016 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18634022, 9887333, 31741144). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 481349). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 2016 of the ATM protein (p.Asp2016Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2017 | The p.D2016V variant (also known as c.6047A>T), located in coding exon 40 of the ATM gene, results from an A to T substitution at nucleotide position 6047. The aspartic acid at codon 2016 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. A similar alteration affecting this same amino acid, p.D2016G, has been reported in a homozygous state in ataxia telangiectasia (A-T) patients of German and Iranian descent (Sandoval N et al. Hum Mol Genet. 1999;8(1):69-79; Babaei M et al. Hum Genet. 2005;117(2-3):101-6), and in combination with an ATM truncating mutation in a Turkish A-T patient (Demuth I et al. Neurogenetics. 2011;12(4):273-82). 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