11-108235839-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000051.4(ATM):c.496+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,422 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: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ATM
NM_000051.4 splice_donor_5th_base, intron
NM_000051.4 splice_donor_5th_base, intron
Scores
1
7
Splicing: ADA: 0.9992
2
Clinical Significance
Conservation
PhyloP100: 2.62
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-108235839-G-A is Pathogenic according to our data. Variant chr11-108235839-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108235839-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.496+5G>A | splice_donor_5th_base_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.496+5G>A | splice_donor_5th_base_variant, intron_variant | NM_000051.4 | ENSP00000501606 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727034
GnomAD4 exome
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31
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GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 16, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change falls in intron 5 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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with an attenuated form of ataxia-telangiectasia and/or prostate cancer (PMID: 15054841, 19535770, 35534218). ClinVar contains an entry for this variant (Variation ID: 3047). 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 5, but is expected to preserve the integrity of the reading-frame (PMID: 15054841; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2023 | Variant summary: ATM c.496+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. At least one publication reports experimental evidence indicating that this variant results in skipping of exon 5 (Dork_2004) and another suggests that this variant results in leaky splicing (Bueno-Martinez_2022). The variant was absent in 251312 control chromosomes. c.496+5G>A has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Dork_2004, Verhagen_2009). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35716007, 15054841, 19535770). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 01, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2022 | The c.496+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 4 in the ATM gene. This alteration has been reported in German and Dutch ataxia-telangiectasia patients, both of whom were described as having a mild or attenuated phenotype with onset occurring in adulthood (Dörk T et al. Am. J. Med. Genet. 2004 Apr;126A(3):272-7; Verhagen MM et al. Neurology 2009 Aug;73(6):430-7). Functional analysis of cDNA from the patient's lymphoblastoid cell line by Dörk T et al. revealed an in-frame deletion of coding exon 4 (described as exon 7 in the manuscript). 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 12, 2021 | This variant causes a G>A nucleotide substitution at the +5 position of intron 5 of the ATM gene. This variant is also known as IVS7+5G>A in the literature. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA study on carrier-derived lymphoblastoid cells showed the skipping of exon 5, resulting in an in-frame deletion of 165 bases (PMID: 15054841), while ATM protein levels were reduced to less than 20% of wild-type (PMID: 15054841, 21778326). Functional studies found moderate radial sensitivity and chromosomal instability (PMID: 15054841, 19535770) and severe disruption to kinase activity (PMID: 21778326). This variant has been observed in compound heterozygous state with known pathogenic c.7875_7876delTGinsGC (p.Asp2625_Ala2626delinsGluPro) variant in at least two individuals affected with an atypical, attenuated form of ataxia-telangiectasia (PMID: 15054841, 19535770, 28126470, 30549301). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Ataxia - telangiectasia variant Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 30, 2004 | - - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2023 | Observed with an ATM pathogenic variant in individuals with ataxia telangiectasia (AT) in published literature and at GeneDx (PMID: 15054841, 19535770, 37438524); Observed in an individual with endometrial cancer (PMID: 32775946); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 15054841, 16189143, 19535770, 22213089, 28126470, 31050087, 21778326, 30549301, 35534218, 37438524, 35716007, 32775946) - |
Familial cancer of breast Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Mar 20, 2018 | This sequence variant is a single nucleotide substitution (G>A) that occurs at the +5 position of intron 5 of the ATM gene. This variant has not been observed in the Exome Aggregation Consortium (ExAC) database. RNA analysis indicates that c.496+5G>A causes a splicing defect leading to an in-frame deletion of exon 5 (identified in the publication as exon 7), shortening the RNA by 165 nucleotides (PMID: 15054841) and the protein by 55 amino acid residues (p.Arg111_Glu166del55insLys). This shortened protein deriving from the variant has a decrease to only 20-40% of the expression of a wild-type variant, and cells had markedly reduced phosphorylation activity toward p53 and NBS1/p95 after radiation exposure (PMID: 15054841). ATM:c.496+5G>A is found in the case described in this paper, as well as two unrelated families affected by ataxia-telangiectasia (A-T). In the two documented cases of A-T where the variant was present, it was also found to be compound heterozygous with known pathogenic variant c.7875_7876delTGinsGC (p.Asp2625_Ala2626delinsGluPro). Despite the clear association of ATM:c.496+5G>A with risk for A-T, its association with hereditary cancer is less clear. Based on these data, we consider this variant to be likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MutationTaster
Benign
D;D
Sift4G
Benign
T
Vest4
MVP
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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
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