chr11-108307884-TTTTG-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000051.4(ATM):c.5675-7_5675-4delTTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,602,366 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000051.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5675-7_5675-4delTTGT | splice_region_variant, intron_variant | Intron 37 of 62 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250386Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135340
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1450270Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 722218
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74290
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2Uncertain:1
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This sequence change falls in intron 37 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 altered protein product. This variant is present in population databases (no rsID available, 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: 453597). Studies have shown that this variant results in exon 38 skipping, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: ATM c.5675-7_5675-4delTTGT 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: Two predict the variant abolishes a 3' acceptor site. One predicts the variant weakens a 3' acceptor site. One predicts the variant no significant impact on splicing. Internal RNA splicing evidence shows that this variant affects mRNA splicing in at least 2 individuals resulting in out of frame skipping of exon 38, predicted to lead to nonsense mediated decay (Labcorp, formerly Invitae). The variant allele was found at a frequency of 4e-06 in 250386 control chromosomes. c.5675-7_5675-4delTTGT has been reported in the presumed compound heterozygous state in the literature in at least 1 individual affected with Ataxia-Telangiectasia (example, Zielen_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34477998). ClinVar contains an entry for this variant (Variation ID: 453597). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1Uncertain:2
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RNA studies demonstrate aberrant splicing (External communication with Invitae and Ambry Genetics); Observed in an individual with ataxia-telangiectasia who also harbored a second ATM variant; however, it is unknown whether the variants are on the same or opposite chromosomes (in cis or trans) (PMID: 34477998); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34477998) -
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded inconclusive predictions regarding the effect of this variant on RNA splicing. -
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
The c.5675-7_5675-4delTTGT intronic variant, located in intron 36 of the ATM gene, results from a deletion of 4 nucleotides within intron 36 of the ATM gene. This nucleotide region is well conserved in available vertebrate species. This variant has been reported in conjunction with a missense ATM mutation in a patient with ataxia-telangiectasia (Zielen S et al. J Clin Immunol 2021 Nov;41(8):1878-1892). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
This variant deletes 4 nucleotides of intron 37 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000622616.8). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at