rs1060501621
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000675843.1(ATM):c.332-2_332delAGG(p.Arg111fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,214 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R111R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000675843.1 frameshift, splice_acceptor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.332_334delGAG | p.Arg111_Ala112delinsThr | disruptive_inframe_deletion, splice_region_variant | 5/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1450214Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 722138
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 22, 2023 | The c.332_334delGAG variant (also known as p.R111_A112delinsT) is located in coding exon 4 of the ATM gene. This variant results from an in-frame GAG deletion at nucleotide positions 332 to 334. The arginine and alanine at codons 111 and 112 are replaced by threonine, an amino acid with similar properties. However, this change occurs in the first base pair of coding exon 4, which means it may have some effect on normal mRNA splicing. This variant has been detected in conjunction with an ATM pathogenic variant in an individual diagnosed with ataxia-telangiectasia; however, the phase of the two variants was not specified (Sasaki T et al. Hum Mutat, 1998;12:186-95). In addition, it was reported that RNA studies demonstrated that this alteration caused abnormal splicing in the sample tested (Sasaki T et al. Hum Mutat, 1998;12:186-95). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). In addition, as a deletion-insertion the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 24, 2018 | - - |
Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This variant, c.332_334del, is a complex sequence change that results in the deletion of 2 amino acids and insertion of 1 amino acid(s) in the ATM protein (p.Arg111_Ala112delinsThr). 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: 407594). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (Invitae). 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