rs375190373
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):c.4792C>A(p.Leu1598Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L1598L) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4792C>A | p.Leu1598Ile | missense_variant | 32/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4792C>A | p.Leu1598Ile | missense_variant | 32/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251238Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135780
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461526Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727084
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74306
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1598 of the ATM protein (p.Leu1598Ile). This variant is present in population databases (rs375190373, gnomAD 0.02%). 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: 181962). 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 disruptive. 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 | Revvity Omics, Revvity | Mar 29, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 22, 2022 | The ATM c.4792C>A (p.Leu1598Ile) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-108165669-C-A?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia or hereditary breast cancer. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 24, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 08, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 13, 2023 | This missense variant replaces leucine with isoleucine at codon 1598 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 4/282630 chromosomes 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 | Jun 24, 2023 | The p.L1598I variant (also known as c.4792C>A), located in coding exon 31 of the ATM gene, results from a C to A substitution at nucleotide position 4792. The leucine at codon 1598 is replaced by isoleucine, an amino acid with highly similar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2023 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 24, 2022 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 14, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at