Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 13147 nt | 386–9556 |
| NM_000051.4 | MANE Select | 12915 nt | 151–9321 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (6 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.12 | -10 bp |
| Donor Loss (DL) | 0.0 | 134 bp |
| Acceptor Gain (AG) | 0.01 | -186 bp |
| Donor Gain (DG) | 0.01 | -111 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Use ATM PVS1 Decision Tree (gene-specific)". The evidence for this variant shows: c.3154-4G>T is at position –4 relative to the exon and is outside the canonical ±1-2 splice sites. Therefore, this criterion is not applied because the variant does not meet the gene-specific PVS1 splice site requirements.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Use for protein changes as long as splicing is ruled-out for both alterations." The evidence for this variant shows: c.3154-4G>T does not alter the protein sequence and there is no known identical amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Use functional studies when a variant fails to rescue ATM-specific features AND radiosensitivity (Moderate) or fails to rescue an ATM-specific feature only (Supporting)." The evidence for this variant shows: no functional characterization studies exist for c.3154-4G>T. Therefore, this criterion is not applied due to absence of functional data.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Case-control data with significant association (OR ≥2 and p≤0.05)." The evidence for this variant shows: no case-control or statistical association data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation." The evidence for this variant shows: c.3154-4G>T lies outside known functional domains/hot spots. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Frequency ≤0.001% if n=1 in a single subpopulation." The evidence for this variant shows: global MAF=0.00142% (4/282 472 alleles, >1 allele in multiple subpopulations). Therefore, this criterion is not applied because the allele frequency exceeds the VCEP threshold for PM2_supporting.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Evidence of trans configuration with a pathogenic variant in recessive disorders." The evidence for this variant shows: no compound heterozygosity or trans data available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: c.3154-4G>T does not alter coding sequence length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5_supporting is: "Genomic frameshift/truncating variants with PTC upstream of p.R3047 or splice variants causing PTC with NMD." The evidence for this variant shows: c.3154-4G>T is an intronic variant without PTC generation. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism." The evidence for this variant shows: it is intronic and not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting if protein REVEL>0.7333 or RNA: at least one predictor shows splicing impact." The evidence for this variant shows: SpliceAI maximum score 0.12 (below typical significance), CADD -0.18, indicating no deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic but evidence not available." The evidence for this variant shows: no reputable source reports pathogenicity. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency >0.5%." The evidence for this variant shows: global MAF=0.00142%, well below 0.5%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Filtering allele frequency >0.05%." The evidence for this variant shows: global MAF=0.00142%, below 0.05%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals for a recessive condition." The evidence for this variant shows: no data on healthy adult observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Functional studies showing rescue of ATM-specific features (Moderate/Supporting)." The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows: it is intronic and not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observation in trans with a pathogenic variant in an autosomal dominant disorder." The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function." The evidence for this variant shows: it is an intronic SNV. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting if protein REVEL ≤0.249 OR RNA: at least one predictor shows no splicing impact." The evidence for this variant shows: SpliceAI score 0.12 (below significance), CADD -0.18 indicating no deleterious effect. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict no impact on splicing or protein function.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such context. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Likely benign by six laboratories without accessible evidence. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or deep intronic variants >+7 or <−40 that have no predicted splice impact." The evidence for this variant shows: it is at –4, within the splicing region. Therefore, this criterion is not applied.