11-108293478-GTAATAAAAATTT-G
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000051.4(ATM):c.4776+2_4776+13del variant causes a splice donor, splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000000687 in 1,455,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ATM
NM_000051.4 splice_donor, splice_donor_5th_base, intron
NM_000051.4 splice_donor, splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.88
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 12 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017882455 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108293478-GTAATAAAAATTT-G is Pathogenic according to our data. Variant chr11-108293478-GTAATAAAAATTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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ATM | NM_000051.4 | c.4776+2_4776+13del | splice_donor_variant, splice_donor_5th_base_variant, intron_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4776+2_4776+13del | splice_donor_variant, splice_donor_5th_base_variant, intron_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249594Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135006
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GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455982Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 724706
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GnomAD4 genome Cov.: 30
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 24, 2024 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 08, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2022 | This variant causes a 12 nucleotide deletion affecting a canonical splice site in intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/249594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2024 | The c.4776+2_4776+13del12 intronic pathogenic mutation, located in intron 30 of the ATM gene, results from a deletion of 12 nucleotides within intron 30 of the ATM gene. This nucleotide region is well 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). In addition, multiple ATM mutations affecting this canonical splice donor site (c.4776+2T>C, c.4776+2T>A, c.4776+2T>C), have been reported in patients with ataxia telangiectasia and have also been shown to result in skipping of coding exon 30 (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62(3):551-61; Ejima Y et al. Hum. Genet., 1998 Apr;102:403-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Ataxia-telangiectasia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change affects a splice site in intron 31 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs762838462, gnomAD 0.0009%). 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: 420098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2015 | This variant is denoted ATM c.4776+2_4776+13del12 or IVS31+2_IVS31+13del12 and consists of a deletion of 12 nucleotides from the +2 to +13 positions of intron 31. The normal sequence, with the bases that are deleted in braces, is GAGg[del12]catc, where the capital letters are exonic and lowercase are intronic. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider ATM c.4776+2_4776+13del12 to be likely pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at