rs3092910
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000051.4(ATM):c.5793T>C(p.Ala1931Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 1,613,558 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0060 ( 6 hom., cov: 32)
Exomes 𝑓: 0.0068 ( 35 hom. )
Consequence
ATM
NM_000051.4 synonymous
NM_000051.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.136
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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 11-108310190-T-C is Benign according to our data. Variant chr11-108310190-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108310190-T-C is described in Lovd as [Likely_benign]. Variant chr11-108310190-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.136 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00604 (920/152308) while in subpopulation EAS AF= 0.0106 (55/5184). AF 95% confidence interval is 0.00837. There are 6 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.5793T>C | p.Ala1931Ala | synonymous_variant | 39/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.00605 AC: 921AN: 152190Hom.: 6 Cov.: 32
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GnomAD3 exomes AF: 0.00506 AC: 1271AN: 251034Hom.: 4 AF XY: 0.00488 AC XY: 663AN XY: 135732
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GnomAD4 exome AF: 0.00685 AC: 10005AN: 1461250Hom.: 35 Cov.: 31 AF XY: 0.00664 AC XY: 4825AN XY: 726946
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GnomAD4 genome 0.00604 AC: 920AN: 152308Hom.: 6 Cov.: 32 AF XY: 0.00565 AC XY: 421AN XY: 74484
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:27
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant not near splice site - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 25, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 08, 2015 | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 29, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
not provided Benign:6
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 07, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | ATM: BP4, BP7, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Ataxia-telangiectasia syndrome Benign:4
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 02, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Jun 28, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 20, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 04, 2015 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 10, 2015 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 27, 2021 | - - |
Familial cancer of breast Benign:2
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 24, 2024 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
ATM-related disorder Benign:1
| Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 15, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Malignant tumor of breast Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Ala1931= variant was identified in 3 of 572 proband chromosomes (frequency: 0.005) from North American caucasian and American Indian individuals or families with Non-Hodgkin’s Lymphoma, or undisclosed cancer; and was present in 1 of 186 control chromosomes (frequency: 0.005) from healthy individuals (Sipahimalani 2007, Petereit 2013, Thorstenson 2001). Thorstenson et al (2001) showed that ATM shows overall low sequence diversity, when compared across 7 major human populations. The variant was also identified in dbSNP (ID: rs3092910) “With other allele”, ClinVar (classified as benign by Invitae, GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Color Genomics Inc; and likely benign by Ambry Genetics, Prevention Genetics, Praxis fuer Humangenetik Tuebingen, Lab. for Molecular Medicine Partners HealthCare Personalized Medicine, and Genetic Services Laboratory (U of Chicago)), Clinvitae (5x), and was not identified in Genesight-COGR, Cosmic, MutDB, LOVD 3.0, and ATM-LOVD. The variant was identified in control databases in 1400 (6 homozygous) of 276860 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 191 (1 homozygous) of 24012 chromosomes (frequency: 008), Other in 27 of 6450 chromosomes (frequency: 004), Latino in 45 of 34376 chromosomes (frequency: 001), European Non-Finnish in 828 (3 homozygous) of 126508 chromosomes (frequency: 007), Ashkenazi Jewish in 31 of 10146 chromosomes (frequency: 003), East Asian in 213 (2 homozygous) of 18848 chromosomes (frequency: 01), European Finnish in 20 of 25750 chromosomes (frequency: 0008), and South Asian in 45 of 30770 chromosomes (frequency: 001). The p.Ala1931= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at