chr11-108293478-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.4776+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. 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. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000051.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4776+1G>T | splice_donor_variant | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4776+1G>T | splice_donor_variant | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455982Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 724706
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs771117943, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 9497252, 12815592, 20840352, 31050087). ClinVar contains an entry for this variant (Variation ID: 478920). Experimental studies have shown that disruption of this splice site affects ATM function (PMID: 2491181, 9497252). Studies have shown that disruption of this splice site results in skipping of 31, but is expected to preserve the integrity of the reading-frame (PMID: 31050087). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2023 | The c.4776+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 30 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This mutation has been seen in conjunction with another pathogenic ATM mutation in a 9 year old female with severe ataxia-telangiectasia (A-T) (Broccoletti T et al. Eur. J. Neurol. 2011 Apr;18:564-70). In another study, this alteration was identified with a missense ATM alteration in an individual with atypical A-T and was reported to cause skipping of coding exon 30 (Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730). 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). 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 | Aug 09, 2023 | This variant causes a G to T nucleotide substitution at the +1 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing and is expected to result in a disrupted protein product. This variant has been reported in unknown phase with a pathogenic ATM variant, c.748C>T (p.Arg250Ter), in an individual affected with classic ataxia-telangiectasia (PMID: 20840352, 22763152). This variant has also been reported in the compound heterozygous state in an individual affected with atypical ataxia-telangiectasia (PMID: 31050087). Lymphoblastoid cell lines derived from this individual showed in-frame skipping of exon 31 (PMID: 31050087). This variant was reported in an individual affected with ovarian cancer (PMID: 34371384). This variant has been identified in 1/244648 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. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 26, 2022 | - - |
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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2020 | Canonical splice site variant demonstrated to result in an in-frame deletion of exon 31 (Fivet 2019); Observed in an individual with familial breast cancer; however, the variant was not found in an affected sister (Bubien 2017); Observed with other ATM variants in unrelated patients with ataxia-telangiectasia, but it was not reported whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Broccoletti 2011, Fivet 2019); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31050087, 22763152, 28691344, 20840352) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at