rs199543313
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.3154-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,613,642 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 4 hom. )
Consequence
ATM
NM_000051.4 splice_region, intron
NM_000051.4 splice_region, intron
Scores
2
Splicing: ADA: 0.00003800
2
Clinical Significance
Conservation
PhyloP100: 0.439
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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 11-108272718-G-A is Benign according to our data. Variant chr11-108272718-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142254.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=8, Benign=6}. Variant chr11-108272718-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000229 (334/1461600) while in subpopulation MID AF= 0.012 (69/5764). AF 95% confidence interval is 0.0097. There are 4 homozygotes in gnomad4_exome. There are 187 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.3154-4G>A | splice_region_variant, intron_variant | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000224 AC: 34AN: 151924Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000203 AC: 51AN: 251096Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135758
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GnomAD4 exome AF: 0.000229 AC: 334AN: 1461600Hom.: 4 Cov.: 32 AF XY: 0.000257 AC XY: 187AN XY: 727108
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GnomAD4 genome 0.000224 AC: 34AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:5
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2014 | 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 | Jan 25, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 23, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 04, 2024 | Variant summary: ATM c.3154-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 1613642 control chromosomes in the gnomAD database, including 4 homozygotes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00023 vs 0.004), however the presence of homozygotes in controls suggest the variant could be benign. c.3154-4G>A has been reported in the literature as a VUS in settings of multigene panel testing among in individuals undergoing testing for Lynch and/or associated cancers (example, Yurgelun_2015, Grant_2015, Tung_2014, Pereira_2022). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.1670T>G, p.Leu557X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25479140, 25186627, 25980754, 35980532, 34299313, 32658311). ClinVar contains an entry for this variant (Variation ID: 142254). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 28, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | ATM: BP4 - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 10, 2015 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 26, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2018 | 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. - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | - - |
Familial cancer of breast Benign:2
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 13, 2024 | This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 25, 2023 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM c.3154-4G>A variant was identified in 2 of 3100 proband chromosomes (frequency: 0.0006) from individuals or families with Lynch Syndrome and pancreatic cancer (Yurgelun 2015, Grant 2015). The variant was identified in dbSNP (rs199543313) as “with uncertain significance allele”, ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color; as benign by GeneDx; and as uncertain significance by Integrated Genetics) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 53 of 282,472 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 7206 chromosomes (freq: 0.0004), European in 36 of 128962 chromosomes (freq: 0.0003), Ashkenazi Jewish in 2 of 10,358 chromosomes (freq: 0.0002), Latino in 6 of 35,420 chromosomes (freq: 0.0002), South Asian in 4 of 30,602 chromosomes (freq: 0.0001), and African in 2 of 24,920 chromosomes (freq: 0.00008), while it was not observed in the East Asian or Finnish populations. The c.3154-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, nor does it affect positions -3 and -5 to -12, which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, c.3154-4G>A is a non-highly conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at