rs752135143
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000051.4(ATM):c.331+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ATM
NM_000051.4 splice_region, intron
NM_000051.4 splice_region, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 7.24
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 Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108229328-G-A is Pathogenic according to our data. Variant chr11-108229328-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108229328-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.331+5G>A | splice_region_variant, intron_variant | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.331+5G>A | splice_region_variant, intron_variant | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249372Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134892
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1456716Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 724808
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and published functional studies demonstrate this variant causes skipping of exon 4, with reduced or absent ATM protein and kinase activity (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; van Os et al., 2017); Observed in the homozygous or compound heterozygous state in several individuals with ataxia-telangiectasia (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; Chen et al., 2013; van Os et al., 2017); Observed in the heterozygous state in individuals with prostate or ovarian cancer (Lilyquist et al., 2017; Darst et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also reported as IVS6+5G>A using alternate intron nomenclature; This variant is associated with the following publications: (PMID: 23726790, 22006793, 19535770, 23566627, 22213089, 28126470, 19705055, 30549301, 29288088, 32853339, 29922827, 30850667, 37649078, 28888541) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 18, 2022 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Ataxia-telangiectasia syndrome Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 29, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.331+5G>A variant in ATM has been reported in at least 2 homozygous and 2 compound heterozygous individuals with ataxia-telangiectasia and segregated with disease in at least 1 affected family member (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793, Verhagen 2012 PMID: 22213089, Chen 2013 PMID: 23726790). It has also been reported in ClinVar (Variation ID 230851) but was absent from large population studies. This variant is located in the 5'/3' splice region. Computational tools do not provide strong support for a splicing impact, however, In vitro functional studies (including using patient tissue) support exon 6 (exon 5 on NM000051) skipping (introducing a frameshift) and an impact on ATM function (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793). Loss of function of the ATM gene is an established disease mechanism in autosomal recessive ataxia telangiectasia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ataxia telangiectasia. ACMG/AMP Criteria applied: PM2_supporting, PVS1, PM3_Strong. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change falls in intron 4 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs752135143, gnomAD 0.0009%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 19535770, 22006793, 22213089, 23726790). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 230851). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 19535770). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Splice variant predicted to produce a truncated protein by alternate splicing. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19535770). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 19535770, 22213089, 23726790). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 23726790). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230851 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Familial cancer of breast Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 09, 2024 | This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data, PMID: 17726045]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19535770, 22213089, 23726790]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Aug 26, 2024 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 23, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2021 | The c.331+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the ATM gene. In one study, this alteration was detected as homozygous in two related individuals diagnosed with ataxia-telangiectasia (A-T) and was correlated with decreased ATM protein levels and kinase activity (Verhagen MM et al, Neurology 2009 Aug; 73(6):430-7). This alteration has also been identified in several individuals with A-T as a compound heterozygous state (Morio T et al. Int. J. Hematol., 2009 Nov;90:455-462; Nakamura K et al. Hum. Mutat., 2012 Jan;33:198-208; Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71; Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at