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""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.69 | -176 bp |
| Donor Loss (DL) | 0.9 | -2 bp |
| Acceptor Gain (AG) | 0.0 | 25 bp |
| Donor Gain (DG) | 0.05 | 25 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength"; The evidence for this variant shows: c.4611+2T>C affects the canonical +2 splice donor site in ATM, predicted to abolish normal splicing in a gene where loss of function is a known mechanism; Therefore, this criterion is applied at Very Strong strength because the variant disrupts a canonical splice site per the ATM-specific PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, "Strong Strength: Strong Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect."; The evidence for this variant shows: this is a splice site alteration, not a protein-level identical amino acid change; Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history of the disease"; The evidence for this variant shows: no de novo occurrence data are available; Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, "Moderate Strength: Moderate Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity"; The evidence for this variant shows: no functional assay data (e.g. kinase activity or splicing assays) are available; Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, "Strong Strength: Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5)"; The evidence for this variant shows: no case-control or proband frequency data are available; Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, "PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation"; The evidence for this variant shows: c.4611+2T>C is a splice site variant, not within a defined protein domain; Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population"; The evidence for this variant shows: absent from population databases (gnomAD MAF=0%); Therefore, this criterion is applied at Supporting strength because the variant is extremely rare per ATM-specific frequency threshold.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies to recessive diseases when detected in trans with a pathogenic variant; The evidence for this variant shows: no trans phasing data with another pathogenic ATM variant; Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, "PM4: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants"; The evidence for this variant shows: it is a splice site variant without defined in-frame coding change upstream of stop codon; Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047"; The evidence for this variant shows: no specific PTC location data relative to p.R3047 or high-quality splicing impact data; Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, "PM6: Assumed de novo, but without confirmation of paternity and maternity"; The evidence for this variant shows: no assumed de novo data; Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, "PP1: Co-segregation with disease in multiple affected family members"; The evidence for this variant shows: no family segregation data; Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, "PP2: Missense variant in a gene with a low rate of benign missense variation"; The evidence for this variant shows: it is a splice site variant, not a missense; Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, "Supporting Strength: Supporting RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing"; The evidence for this variant shows: SpliceAI predicts donor loss score of 0.90 indicating significant splicing disruption; Therefore, this criterion is applied at Supporting strength because in silico predictors support a deleterious splicing effect.
PP4 (Not Applied)
According to standard ACMG guidelines, "PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology"; The evidence for this variant shows: no phenotype or clinical data provided; Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, "PP5: Reputable source recently reports variant as pathogenic"; The evidence for this variant shows: not found in ClinVar or other databases; Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, "Stand Alone Strength: Stand Alone Filtering Allele Frequency >.5%"; The evidence for this variant shows: allele frequency is 0%; Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, "Strong Strength: Strong Filtering Allele Frequency >.05%"; The evidence for this variant shows: allele frequency is 0%; Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, "BS2: Observed in healthy adult individuals for a recessive disease with full penetrance"; The evidence for this variant shows: no healthy carrier data; Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, "Supporting Strength: Supporting Use when a variant rescues EITHER an ATM specific feature OR radiosensitivity"; The evidence for this variant shows: no rescue functional data; Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, "BS4: 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, "BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease"; The evidence for this variant shows: it is a splice site variant, not a missense; Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, BP2 applies when observed in cis with a pathogenic variant; The evidence for this variant shows: no cis phasing data; Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, "BP3: In-frame deletions/insertions in a repetitive region"; The evidence for this variant shows: not located in a repetitive region; Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, "BP4: Multiple lines of computational evidence suggest no impact"; The evidence for this variant shows: mixed computational results with high SpliceAI score indicating impact; Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, "BP5: Variant found in a case with an alternate molecular basis for disease"; The evidence for this variant shows: no alternate molecular basis reported; Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, "BP6: Reputable source reports variant as benign"; The evidence for this variant shows: no such report exists; Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, "BP7 applies to synonymous and deep intronic variants beyond ±7/−40 positions"; The evidence for this variant shows: this is a canonical splice site variant at +2; Therefore, this criterion is not applied.