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
OpenThis sequence change affects a donor splice site in intron 21 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 953360). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (3 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) | 0.86 | -76 bp |
| Donor Loss (DL) | 0.93 | -1 bp |
| Acceptor Gain (AG) | 0.0 | 214 bp |
| Donor Gain (DG) | 0.0 | -43 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines for PVS1: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree". The evidence for this variant shows that c.3153+1G>T affects the canonical +1 splice donor site predicted to lead to aberrant splicing and NMD in a gene where loss-of-function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP ATM PVS1 decision tree for canonical splice site variants outside the last exon.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "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 shows this is a splice site variant, not a protein‐level change with splicing ruled out. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no reported de novo observations. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3: "Do not use as strong. Use moderate when a variant fails to rescue both an ATM-specific feature and radiosensitivity." There are no functional studies characterizing this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines for PS4: "Case-control studies; p-value ≤0.05 AND (Odds ratio ≥2 OR lower 95% CI ≥1.5)." No case-control data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines for PM1: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." There is no evidence that this splice site lies in a defined hotspot or functional domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2: "Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation; n>1 would not apply." The variant is absent from gnomAD (frequency = 0%). Therefore, PM2 is applied at Supporting strength because it meets the VCEP rarity threshold.
PM3 (Not Applied)
According to VCEP guidelines for PM3: "Use ATM PM3/BP2 table for recessive observations." There is no evidence of this variant in trans with another pathogenic ATM variant in an affected individual. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame deletions/insertions or stop-loss." This is a splice donor variant, not an in-frame indel or stop-loss. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: "Supporting Strength: frameshift/truncating variants upstream of p.R3047 with observed high-quality splicing impact and NMD prone." While this variant is predicted to truncate upstream of p.R3047, there is no high-quality observed RNA evidence. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6: "Assumed de novo, but without confirmation of paternity and maternity." No such evidence is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines for PP1: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." This is a splice site variant, not a missense. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines for PP3: "Supporting Strength: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing." SpliceAI predicts donor loss (score 0.93). Therefore, PP3 is applied at Supporting strength because the in silico evidence supports deleterious splicing impact.
PP4 (Not Applied)
According to standard ACMG guidelines for PP4: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No phenotype data specific to ATM disease are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: "Reputable source recently reports variant as pathogenic, but evidence is not available." ClinVar reports this variant as 'Likely pathogenic,' not 'Pathogenic.' Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Filtering allele frequency >.5% leads to stand-alone benign classification." The variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Filtering allele frequency >.05% is strong evidence for benign." The variant is absent from population databases. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines for BS2: "Observed in a healthy adult individual for a recessive (homozygous) variant." No such observations exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Use functional rescue data." No functional rescue data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines for BS4: "Lack of segregation in affected members." No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines for BP1: "Missense variant in a gene where only loss-of-function causes disease." This is a loss-of-function splice variant. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP PM3/BP2 table guidance: "Evidence of observation in trans may support benign evaluation." There is no trans observation. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: "In-frame deletions/insertions in repetitive regions." Not applicable to this splice site variant. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4: "Supporting Strength: RNA: At least one predictor shows no impact on splicing." SpliceAI predicts a strong impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5: "Variant found in a case with an alternate molecular basis for disease." No such evidence. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6: "Reputable source reports as benign without underlying evidence." No benign reports exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines for BP7: "Synonymous or deep intronic variants with no predicted impact on splicing." This is a canonical splice site variant. Therefore, BP7 is not applied.