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) | 0.06 | -87 bp |
| Donor Loss (DL) | 0.04 | 77 bp |
| Acceptor Gain (AG) | 0.0 | -77 bp |
| Donor Gain (DG) | 0.01 | 411 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1: Very strong/strong/moderate/supporting use for null variants in ATM. The evidence for this variant shows it is a missense change (D140V), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines for PS1: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no prior pathogenic D140X change at this residue. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed)..." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3 (gene-specific): use when a variant fails to rescue an ATM-specific feature and radiosensitivity. The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines for PS4: "The prevalence of the variant in affected individuals is significantly increased compared to controls." No case-control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines for PM1: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows D140 is not in a recognized ATM mutational hotspot. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines for PM2: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength.
PM3 (Not Applied)
According to VCEP guidelines for PM3 (recessive): "Detected in trans with a pathogenic variant for a recessive disorder." There is no information on a second pathogenic ATM allele or phase. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame indels or stop-loss variants." This is a missense variant without length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines for PM5: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." No pathogenic missense at D140 is reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6: "Assumed de novo, without confirmation of paternity and maternity." No such data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines for PP1: "Cosegregation 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 for PP2: "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease." ATM has known pathogenic and benign missense variation; this does not strongly support benign interpretation. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3: "Protein: REVEL >.7333; RNA: impact on splicing by well-established in silico predictor." The evidence shows mixed computational predictions and SpliceAI score of 0.06 predicting no splice impact. REVEL is not available. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines for PP4: "Patient's phenotype or family history is highly specific for a disease with a single genetic cause." No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: "Reputable source reports variant as pathogenic." The variant is not in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines for BA1: "Allele frequency is >5% in population databases." The variant is absent. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Filtering Allele Frequency >.05%." The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines for BS2: "Observed in healthy adult individuals for a dominant disorder..." No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Use when a variant rescues an ATM-specific feature and/or radiosensitivity." No functional data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines for BS4: "Lack of segregation in affected members of a family." No family data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines for BP1: "Missense variant in a gene for which primarily truncating variants are known to cause disease." ATM has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines for BP2: "Use ATM PM3/BP2 table for cis/trans observations." No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: "In-frame deletions/insertions in a repetitive region without a known function." This is a missense variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4: "Protein Analysis: Metapredictor REVEL score ≤.249 or RNA: no splice impact by well-established predictor." REVEL is unavailable and computational evidence is mixed. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5: "Variant found in a case with an alternate molecular basis for disease." No such data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6: "Reputable source reports variant as benign." No such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines for BP7: "Synonymous variant for which splicing prediction algorithms predict no impact and nucleotide is not highly conserved." This is a missense variant. Therefore, this criterion is not applied.