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) | 0.0 | -358 bp |
| Donor Loss (DL) | 0.0 | 500 bp |
| Acceptor Gain (AG) | 0.03 | 30 bp |
| Donor Gain (DG) | 0.02 | 199 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP PVS1 Decision Tree Modification Type: Gene-specific,Strength, the rule for PVS1 is: "Use ATM PVS1 Decision Tree to evaluate null variants in a gene where LOF is a known mechanism of disease." The evidence for this variant shows it is an intronic change outside of the canonical +/-1,2 splice sites. Therefore, this criterion is not applied because the variant does not create a predicted null effect.
PS1 (Not Applied)
According to VCEP PS1 Splicing table recommendation, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change, with splicing ruled out." The evidence for this variant shows no amino acid change and no previously known pathogenic variant at this site. 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." No de novo or trio data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP PS3 Gene-specific guidelines, the rule for PS3 is: "Use strong only if a variant fails to rescue both an ATM-specific feature and radiosensitivity; moderate if fails both; supporting if fails one ATM-specific feature." No functional studies have been performed 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 with p≤.05 and OR≥2 or lower 95% CI≥1.5." No case-control or proband count data are available. 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‐studied functional domain without benign variation." The variant is intronic outside known functional domains. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP PM2 Gene-specific,Supporting: "Frequency ≤0.001% if n=1 in a single subpopulation." The evidence for this variant shows a gnomAD MAF=0.351% (572/163,016 alleles), well above 0.001%. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP PM3/BP2 table Disease-specific,Gene-specific guidelines, the rule for PM3 is: "Observed in trans with a pathogenic variant in a recessive disorder." No data on trans observations are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP PM4 Gene-specific,Moderate: "Use for stop‐loss variants." This variant is not a stop‐loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP PM5 Gene-specific,Supporting: "Use for novel missense changes at residues with established pathogenic variants or for certain PTC‐inducing splice variants upstream of p.Arg3047." This variant is intronic and does not alter an amino acid. 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 and maternity)." No such data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "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, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." This variant is intronic. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP PP3 Gene-specific,Supporting: "Protein REVEL>0.7333 or RNA: at least one well‐established predictor shows impact on splicing." The evidence shows SpliceAI=0.03, predicting no impact on splicing, and no protein change. 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 is highly specific for a disease with a single genetic etiology." No phenotype data are 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." The variant is not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Stand Alone)
According to VCEP BA1 Disease-specific: "Filtering allele frequency >0.5%." The evidence for this variant shows a Finnish subpopulation MAF=1.23%, exceeding 0.5%. Therefore, this criterion is applied at Stand Alone strength because the allele frequency is too high for a pathogenic variant.
BS1 (Strong)
According to VCEP BS1 Disease-specific: "Filtering allele frequency >0.05%." The evidence for this variant shows overall gnomAD MAF=0.351%, exceeding 0.05%. Therefore, this criterion is applied at Strong strength because the allele frequency is greater than expected for the disorder.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." No data on healthy adult observations are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP BS3 Disease-specific,Gene-specific: "Variant rescues ATM-specific feature and radiosensitivity in functional assay." No rescue data are available. 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 where only LOF causes disease." This variant is intronic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP BP2 Disease-specific,Gene-specific: "Observed in cis with a pathogenic variant in a recessive disorder." No such data are available. 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." This variant is a single nucleotide change. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP BP4 General recommendation: "Protein REVEL ≤0.249 or RNA: at least one predictor shows no impact on splicing." The evidence shows SpliceAI=0.03 predicting minimal splicing impact and CADD=-0.28. Therefore, this criterion is applied at Supporting strength because multiple computational tools indicate no functional impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a gene for which another molecular basis is established for the observed phenotype." No such context is provided. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The variant is not present in any such source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP BP7 General recommendation: "Synonymous and deep intronic variants >+7 or <-40 with no predicted splice impact." This variant is at -30, not beyond -40. Therefore, this criterion is not applied.