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 Uncertain significance (6 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) | 0.04 | 49 bp |
| Donor Loss (DL) | 0.0 | 9 bp |
| Acceptor Gain (AG) | 0.01 | -12 bp |
| Donor Gain (DG) | 0.0 | 165 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease. The evidence shows: NM_000051.4:c.5509T>G is a missense variant, not a null variant. Therefore, this criterion is not applied because the variant type does not meet the null variant definition.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change, as long as splicing is ruled-out. The evidence shows: No previously established pathogenic variant at codon F1837. Therefore, this criterion is not applied due to lack of a known pathogenic amino acid match.
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 shows: No de novo data available. Therefore, this criterion is not applied due to absence of de novo confirmation.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: Use when a variant fails to rescue both an ATM specific feature and radiosensitivity (Strong) or other defined thresholds. The evidence shows: No functional studies available for F1837V. Therefore, this criterion is not applied because functional data are missing.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: Case-control studies with p≤0.05 AND odds ratio ≥2 (lower 95% CI ≥1.5). The evidence shows: No case-control data or case series. Therefore, this criterion is not applied due to lack of statistical association data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: Located in a mutational hot spot or well-established functional domain without benign variation. The evidence shows: No information that F1837 lies in a defined hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: Frequency ≤.001% if n=1 in a single subpopulation (PM2_supporting). The evidence shows: Variant absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the allele frequency meets the rarity threshold.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: Evidence of trans-occurrence with a pathogenic variant in a recessive disorder (strength per table). The evidence shows: No data on compound heterozygosity or trans variants. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: Use for stop-loss variants (Moderate). The evidence shows: F1837V is not a stop-loss variant. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: Novel missense change at a residue with a different pathogenic missense change (Supporting). The evidence shows: No other missense pathogenic variants reported at residue F1837. 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/maternity. The evidence shows: No de novo or family 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 shows: No segregation data 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 variants where missense is a common mechanism of disease. The evidence shows: ATM has many reported pathogenic and benign missense variants. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: REVEL >0.7333 or RNA impact. The evidence shows: REVEL score is 0.32 and SpliceAI predicts no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: Patient phenotype highly specific for a disease with a single genetic etiology. The evidence shows: Clinical phenotype data not provided. 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. The evidence shows: ClinVar lists this variant as VUS. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: Allele frequency >0.5%. The evidence shows: Variant is absent. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: Allele frequency >0.05%. The evidence shows: Variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: Observed in healthy adult with full penetrance expectation. The evidence shows: No such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: Functional studies show rescue of ATM features. The evidence shows: No functional rescue data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: Lack of segregation in affected or segregation in unaffected. The evidence 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 truncating variants cause disease. The evidence shows: Pathogenic missense variants are known in ATM. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: Observed in trans with a pathogenic variant in recessive context. The evidence shows: No data on trans phase. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: In-frame indel in repetitive region without known function. The evidence shows: Variant is missense. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: REVEL ≤0.249 or at least one RNA predictor shows impact. The evidence shows: REVEL is 0.32 and SpliceAI shows no impact. Therefore, this criterion is not applied.
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 shows: No such data. 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 without shared evidence. The evidence shows: ClinVar lists VUS. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: Synonymous or deep intronic variant with no splicing impact. The evidence shows: Variant is missense. Therefore, this criterion is not applied.