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 Likely benign (3 clinical laboratories) and as Benign (2 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) | 0.02 | 19 bp |
| Donor Loss (DL) | 0.0 | -111 bp |
| Acceptor Gain (AG) | 0.04 | 21 bp |
| Donor Gain (DG) | 0.0 | 378 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines: "PVS1: Very Strong Use ATM PVS1 Decision Tree". The variant is intronic at position -9, outside the canonical ±1–2 splice sites with no evidence of aberrant splicing. Therefore, this criterion is not applied because the variant does not meet the gene-specific PVS1 decision tree for loss-of-function.
PS1 (Not Applied)
According to VCEP guidelines: "PS1: Strong Use for protein changes as long as splicing is ruled-out for both alterations." The variant is intronic with no 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)." No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines: "PS3: Strong/Moderate/Supporting strength for functional studies of ATM-specific assays." No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines: "PS4: Strong Case-control studies; p-value ≤.05 AND (OR ≥2)." No case-control or proband frequency data meeting VCEP thresholds 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 without benign variation." The variant is intronic, not within a known hotspot or functional domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines: "PM2: Supporting Strength: Frequency ≤.001% if n=1 in a single sub population." The variant MAF is 0.00743% in gnomAD (17/228,758 alleles, n>1). Therefore, this criterion is not applied because it does not meet the gene-specific rarity threshold.
PM3 (Not Applied)
According to VCEP guidelines: "PM3: Gene-specific rules for recessive trans observations." No evidence of trans observations with a pathogenic variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: "PM4: Protein length changes as a result of in-frame deletions/insertions in a non-repeat region." The variant is intronic. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines: "PM5: Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The variant is intronic. 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." No de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines: "PP1: 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: "PP2: Missense variant in a gene with low rate of benign missense variation." The variant is intronic. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: "PP3: Supporting for REVEL >.7333 or RNA splicing predictor shows impact." SpliceAI score is 0.04, indicating no significant splicing impact, and REVEL is not applicable. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines: "PP4: Patient’s phenotype or family history specifically supports a genetic etiology." No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic but evidence not available." The variant is reported as benign/likely benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: "BA1: Stand Alone Filtering Allele Frequency >.5%." The variant MAF is 0.00743% < 0.5%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: "BS1: Strong Filtering Allele Frequency >.05%." The variant MAF is 0.00743% < 0.05%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines: "BS2: Observed in a healthy adult with full penetrance expected at an early age." No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: "BS3: Functional studies show no damaging effect." No functional rescue data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines: "BS4: Lack of segregation in affected members of a family." No segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: "BP1: Missense variant in a gene where only truncating variants cause disease." The variant is intronic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines: "BP2: Observed in trans 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: "BP3: In-frame deletions/insertions in a repetitive region without a known function." The variant is intronic. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines: "BP4: Multiple lines of computational evidence suggest no impact on gene or gene product." SpliceAI predicts no impact on splicing (max score 0.04) and no other in silico tools suggest deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports no splicing or functional impact.
BP5 (Not Applied)
According to standard ACMG guidelines: "BP5: Variant found in a case with an alternate molecular basis for disease." No such case data are available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines: "BP6: Reputable source reports variant as benign, but evidence is not available to the laboratory to perform an independent evaluation." ClinVar entries (3 labs Likely benign, 2 labs Benign) support benign classification but underlying evidence is unavailable. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to standard ACMG guidelines: "BP7: Synonymous or deep intronic variant with no predicted splicing impact located beyond ±7/−40 intronic positions." This variant is at −9, within the intronic region where splice effects cannot be excluded by default. Therefore, this criterion is not applied.