rs786203389
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000051.4(ATM):βc.3693_3695delβ(p.Leu1231_Ser1232delinsPhe) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,547,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 32)
Exomes π: 0.0000022 ( 0 hom. )
Consequence
ATM
NM_000051.4 inframe_deletion
NM_000051.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.49
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_000051.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3693_3695del | p.Leu1231_Ser1232delinsPhe | inframe_deletion | 25/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.3693_3695del | p.Leu1231_Ser1232delinsPhe | inframe_deletion | 25/63 | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248448Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134418
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GnomAD4 exome AF: 0.00000215 AC: 3AN: 1394842Hom.: 0 AF XY: 0.00000143 AC XY: 1AN XY: 697386
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This variant, c.3693_3695del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the ATM protein (p.Leu1231_Ser1232delinsPhe). This variant is present in population databases (rs786203389, gnomAD 0.003%). 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: 186997). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 04, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2023 | The c.3693_3695delATC variant (also known as p.L1231_S1232delinsF) is located in coding exon 24 of the ATM gene. This variant results from an in-frame deletion of 3 nucleotides at positions 3693 and 3695. This results in the deletion of a leucine and serine between codons 1231 and 1232 and replacement by a phenylalanine. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (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 | Mar 24, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of two amino acids and insertion of one different amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19781682) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at