rs1555137929
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000051.4(ATM):c.8419G>A(p.Glu2807Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,448,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 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. E2807D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8419G>A | p.Glu2807Lys | missense_variant, splice_region_variant | 58/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.8419G>A | p.Glu2807Lys | missense_variant, splice_region_variant | 58/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1448738Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 721326
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 04, 2021 | This missense variant replaces glutamic acid with lysine at codon 2807 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing, although this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 17, 2019 | The p.E2807K variant (also known as c.8419G>A) is located in coding exon 57 of the ATM gene. The glutamic acid at codon 2807 is replaced by lysine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 57. This amino acid position is poorly 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. - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2023 | This variant has not been reported in the literature in individuals affected with ATM-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2807 of the ATM protein (p.Glu2807Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 481050). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at