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) | 0.01 | -59 bp |
| Donor Loss (DL) | 0.0 | 16 bp |
| Acceptor Gain (AG) | 0.0 | -224 bp |
| Donor Gain (DG) | 0.0 | 229 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". The evidence for this variant shows that it is a missense change (L1046P) and not a null variant. Therefore, this criterion is not applied because missense variants do not qualify for PVS1 under the ATM-specific decision tree.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no previously established pathogenic variant at residue L1046. 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." De novo status is unknown for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity." No functional studies are available for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Case-control studies; p-value ≤0.05 AND (Odds ratio ≥2 OR lower 95% CI ≥1.5)." No case-control data exist for this variant. 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 and/or critical and well-established functional domain without benign variation." There is no evidence that L1046P lies in a known hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply." The evidence for this variant shows it is absent from gnomAD (0% frequency). Therefore, this criterion is applied at Supporting strength because the variant is extremely rare or absent in population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive inheritance and trans observations." There is no evidence of this variant in trans with a pathogenic variant. 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." L1046P is a missense change, not a length-altering variant. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; supporting for splice variants." L1046P is a missense change unrelated to PTCs. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "De novo (without confirmation of paternity and maternity)." De novo status is unknown. 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." No segregation data are available. 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 a low rate of benign missense variation and in which missense variants are a common mechanism of disease." ATM has both benign and pathogenic missense variants, and there is insufficient evidence to apply PP2 here. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Protein: REVEL >.7333; RNA: at least one well-established in silico predictor shows impact on splicing." Computational evidence for L1046P is mixed-to-benign (CADD=4.95, PrimateAI benign, SpliceAI minimal). Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." 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 recently reports variant as pathogenic or likely pathogenic." The variant is not present in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Filtering Allele Frequency >.5%." Frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Filtering Allele Frequency >.05%." Frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." No healthy adult observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Use when a variant rescues both an ATM specific feature and radiosensitivity (Moderate) or either one (Supporting)." No functional rescues are reported. 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." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." ATM disease mechanism includes missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Use ATM PM3/BP2 table for observations in trans with a pathogenic variant." No such observations exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." L1046P is not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Protein Analysis: Metapredictor REVEL score ≤.249; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing." The evidence for this variant shows benign computational predictions (CADD=4.95, PrimateAI benign) and SpliceAI ≤0.01. Therefore, this criterion is applied at Supporting strength because multiple computational lines support no impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular cause of disease." No such cases are reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign." No such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant or deep intronic with no splicing impact." L1046P is a missense variant. Therefore, this criterion is not applied.