chr11-108317373-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_000051.4(ATM):c.6199G>T(p.Ala2067Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. A2067D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6199G>T | p.Ala2067Ser | missense_variant, splice_region_variant | 43/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.6199G>T | p.Ala2067Ser | missense_variant, splice_region_variant | 43/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458700Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725766
GnomAD4 genome Cov.: 28
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2067 of the ATM protein (p.Ala2067Ser). This variant is not present in population databases (gnomAD no frequency). 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: 923304). 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. This variant disrupts the p.Ala2067 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9887333, 22345219, 25914063; Invitae). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 13, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at