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 Benign (2 clinical laboratories) and as Likely benign (1 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) | 0.16 | 43 bp |
| Donor Loss (DL) | 0.0 | -66 bp |
| Acceptor Gain (AG) | 0.06 | 25 bp |
| Donor Gain (DG) | 0.03 | -68 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree". The evidence for this variant shows it is an intronic duplication at position -18, outside the canonical splice acceptor/donor sites and with no predicted effect on splicing. Therefore, this criterion is not applied because the variant does not meet any of the loss-of-function categories in the ATM PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 applies to protein changes with identical amino acid alteration. The evidence for this variant shows no change to the encoded amino acid (intronic duplication). 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. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Moderate Strength: Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity; Supporting Strength: Use when it fails to rescue an ATM specific feature only." The evidence for this variant shows no functional studies assessing ATM activity. Therefore, this criterion is not applied due to lack of functional data.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control data)." The evidence for this variant shows no case-control studies. 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 evidence for this variant shows it is an intronic duplication, not in a known functional domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Frequency ≤ 0.001% if n=1 in a single subpopulation; n>1 in one or multiple subpopulations would not be considered rare." The evidence for this variant shows a MAF of 0.00759% with 19 alleles observed. Therefore, this criterion is not applied because the frequency exceeds the VCEP threshold.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows no data on trans occurrence in recessive cases. 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 in non-repeat regions." The evidence for this variant shows an intronic duplication not predicted to alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; apply to splice variants only when PVS1_VS(RNA) applies." The evidence for this variant shows neither a truncating event nor demonstrated splice impact. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and 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 a low rate of benign missense variation and where missense is a common mechanism." This is an intronic duplication, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein REVEL >0.7333 or RNA: predictor shows impact on splicing." The evidence for this variant shows SpliceAI predicts no significant splicing impact. 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." The evidence for this variant shows no phenotype data. 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 ClinVar reports benign/likely benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand-alone: Filtering allele frequency >0.5%." The evidence for this variant shows a MAF of 0.00759%, well below the threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filtering allele frequency >0.05%." The evidence for this variant shows a MAF of 0.00759%, below the threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder." The evidence for this variant shows no data on observation in unaffected individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Moderate: Functional studies show rescue of ATM features AND radiosensitivity; Supporting: rescue of either feature." The evidence for this variant shows no functional studies. 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 loss-of-function causes disease." This is an intronic duplication, not a missense. 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." The evidence for this variant shows no such 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 region without a known function." The evidence for this variant shows an intronic duplication not in a repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Protein Analysis: Metapredictor REVEL score ≤ .249; RNA: no predicted impact on splicing (e.g., SpliceAI)." The evidence for this variant shows SpliceAI predicts no significant effect on splicing (max delta score 0.16). Therefore, this criterion is applied at Supporting strength because computational evidence indicates no deleterious impact.
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 alternate cause reported. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but evidence not available." The evidence for this variant shows ClinVar entries: Benign (2 labs) and Likely benign (1 lab). Therefore, this criterion is applied at Supporting strength because a reputable source classifies it as benign.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7_(RNA) is: "Supporting for synonymous and deep intronic variants defined as >+7 or <-40 from splice sites." The evidence for this variant shows it is at -18 from the acceptor site, which is within the splice region. Therefore, this criterion is not applied.