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) | 0.83 | -90 bp |
| Donor Loss (DL) | 0.95 | -1 bp |
| Acceptor Gain (AG) | 0.0 | 3 bp |
| Donor Gain (DG) | 0.0 | -90 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength." The variant is a +1 splice donor site change (c.2466+1G>T) predicted to abolish normal splicing in ATM, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because +1/2 splice variants meeting PVS1 decision tree cause null effect.
PS1 (Not Applied)
According to VCEP guidelines: "Strong Strength: Strong Use for protein changes as long as splicing is ruled-out for both alterations..." The variant is a splice site alteration, not a missense change, so PS1 does not apply.
PS2 (Not Applied)
According to standard ACMG guidelines: PS2 applies to de novo observations with confirmed maternity and paternity. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines: PS3 requires functional studies showing a deleterious effect on ATM-specific features. No functional characterization exists for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines: PS4 requires case-control data with significant association. No such data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines: PM1 applies to variants in well‐established functional domains without benign variation. This splice site does not map to a specific protein domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines: "PM2 Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation..." The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because it is extremely rare or absent in controls.
PM3 (Not Applied)
According to VCEP guidelines: PM3 applies to variants observed in trans with a pathogenic variant in a recessive disorder. No trans or zygosity data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: PM4 applies to protein length changes. This is a splicing variant, not an in‐frame indel or stop-loss. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines: PM5_supporting for premature termination codons upstream of p.Arg3047 with NMD, requiring observed high-quality splicing data. Only in silico predictions exist. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines: PM6 applies to assumed de novo without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines: PP1 requires segregation data in affected family members. No segregation data are provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: PP2 applies to missense in a gene with low rate of benign missense. This is a splice variant. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines: "PP3 Supporting Strength: ...RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing." SpliceAI predicts donor loss (0.95). Therefore, PP3 is applied at Supporting strength because in silico tools support a deleterious splice effect.
PP4 (Not Applied)
According to standard ACMG guidelines: PP4 requires a highly specific phenotype. No phenotype or family history details are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: PP5 applies to variants reported as pathogenic by reputable sources. This variant is not in ClinVar or other databases. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines: BA1 requires allele frequency >5%. The variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines: BS1 requires allele frequency >0.05%. The variant is absent from population databases. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines: BS2 applies when variant observed in healthy adult controls. No such observations exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines: BS3 requires functional studies showing no impact on ATM function. No benign functional data exist. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines: BS4 requires lack of segregation in affected members. No segregation data are provided. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: BP1 applies to missense in a gene where only LOF causes disease. This is a splice variant. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines: BP2 applies to cis observations with pathogenic variants. No phasing data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: BP3 applies to in-frame indels in repetitive regions. Not applicable for a splice variant. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines: BP4 applies when in silico predictors show no impact. SpliceAI predicts high impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines: BP5 applies when variant found in trans or cis with another pathogenic variant causing the phenotype. No such data exist. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines: BP6 applies to reputable source reporting as benign. No such report exists. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines: BP7 applies to synonymous or deep intronic variants >+7/−40. This is a canonical splice donor variant. Therefore, BP7 is not applied.