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 (4 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) | 0.0 | -418 bp |
| Donor Loss (DL) | 0.0 | -140 bp |
| Acceptor Gain (AG) | 0.08 | -121 bp |
| Donor Gain (DG) | 0.05 | -13 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: c.6006+13G>C is located outside the canonical splice site (+1/+2) and is intronic. Therefore, this criterion is not applied because the variant is not predicted to result in loss-of-function per the ATM PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines: "Strong Strength: Strong Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.". The evidence for this variant shows: no amino acid change is produced (intronic), and splicing impact is predicted to be negligible. Therefore, this criterion is not applied because there is no protein-altering change to compare.
PS2 (Not Applied)
According to standard ACMG guidelines: "PS2: Confirmed de novo in a patient with the disease and no family history of the disease.". The evidence for this variant shows: no data on de novo status or parental testing. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3 (Not Applied)
According to VCEP guidelines: "Strong Strength: Strong Do not use as strong. Modification Type: Gene-specific". The evidence for this variant shows: no functional studies assessing ATM-specific feature rescue or radiosensitivity. Therefore, this criterion is not applied because functional evidence is absent.
PS4 (Not Applied)
According to standard ACMG guidelines: "PS4: Case-control studies with p-value ≤0.05 AND (Odds ratio ≥2.0 or lower 95% CI ≥1.5).". The evidence for this variant shows: no case-control or proband frequency data. Therefore, this criterion is not applied due to lack of statistical evidence.
PM1 (Not Applied)
According to standard ACMG guidelines: "PM1: Located in a mutational hot spot or critical and well-established functional domain without benign variation.". The evidence for this variant shows: no evidence that c.6006+13G>C lies in a known hot spot or functional domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply". The evidence for this variant shows: MAF=0.00248% (7/281,860 alleles) across multiple populations. Therefore, this criterion is not applied because the variant frequency exceeds the VCEP threshold for PM2_supporting.
PM3 (Not Applied)
According to VCEP guidelines: "Supporting Strength: Supporting Use ATM PM3/BP2 table". The evidence for this variant shows: no data on trans observations in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines: "Moderate Strength: Moderate Use for stop-loss variants.". The evidence for this variant shows: no stop-loss or protein length change is predicted. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047...". The evidence for this variant shows: no frameshift or truncating effect. 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.". The evidence for this variant shows: no parental inheritance information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines: "PP1: Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: "PP2: Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.". The evidence for this variant shows: intronic change with no missense effect. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: "Supporting Strength: Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing.". The evidence for this variant shows: SpliceAI score=0.08 predicting minimal splicing disruption. Therefore, this criterion is not applied because computational evidence does not support a deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines: "PP4: 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 or family history data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: "PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: reputable sources report it as benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: "Stand Alone Strength: Filtering Allele Frequency >.5%.". The evidence for this variant shows: MAF=0.00248%, below the BA1 threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: "Strong Strength: Filtering Allele Frequency >.05%.". The evidence for this variant shows: MAF=0.00544% (European non-Finnish), below the BS1 threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines: "BS2: Observed in a healthy adult individual for a recessive (homozygous) disorder.". The evidence for this variant shows: no data on homozygous observations in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: "Moderate Strength: Moderate Use when a variant rescues both an ATM specific feature and radiosensitivity.". The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines: "BS4: 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: "BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease.". The evidence for this variant shows: intronic change, no missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines: "Supporting Strength: Supporting Use ATM PM3/BP2 table". The evidence for this variant shows: no cis/trans data with other pathogenic variants. 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 evidence for this variant shows: no indication it lies in a repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines: "Supporting Strength: Supporting 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: SpliceAI predicts no splicing impact (score 0.08) and CADD score -0.08 suggests no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence indicates a benign outcome.
BP5 (Not Applied)
According to standard ACMG guidelines: "BP5: Variant found in a case with an alternate molecular basis for the disease.". The evidence for this variant shows: no such case reported. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines: "BP6: Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar reports it as Likely benign by four clinical laboratories. Therefore, this criterion is applied at Supporting strength because multiple reputable sources classify it as benign without accessible evidence.
BP7 (Supporting)
According to VCEP guidelines: "Supporting Strength: Supporting Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than +7 at donor and further than -40 at acceptor sites.". The evidence for this variant shows: c.6006+13G>C is 13 nucleotides into the intron (beyond +7). Therefore, this criterion is applied at Supporting strength because it qualifies as a deep intronic variant without predicted splicing impact.