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 (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) | 0.01 | -96 bp |
| Donor Loss (DL) | 0.03 | 73 bp |
| Acceptor Gain (AG) | 0.03 | 63 bp |
| Donor Gain (DG) | 0.0 | -401 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 for this variant shows: it is an in‐frame two–amino‐acid deletion/insertion, not a predicted null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant results in the same Q1225_D1226delinsH change. Therefore, this criterion is not applied.
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 for this variant shows: parental testing and de novo status are unknown. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Use when a variant fails to rescue both an ATM‐specific feature (e.g. phosphorylation of ATM‐specific targets) AND radiosensitivity." The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 (Strong) is: "Case‐control studies; p‐value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5)." The evidence for this variant shows: no case‐control or sufficient proband data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation." The evidence for this variant shows: location relative to a defined hotspot or critical domain is unknown. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2_supporting is: "Frequency ≤.001% if n=1 in a single subpopulation, that is sufficiently rare and PM2_supporting would apply." The evidence for this variant shows: absent from controls in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive observations." The evidence for this variant shows: no reports of trans observations in affected individuals. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Use for stop‐loss variants." The evidence for this variant shows: the change is an in‐frame deletion/insertion, not a stop‐loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5_supporting is: "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047." The evidence for this variant shows: it is not a frameshift or truncating variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: de novo status is not assessed. 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 in a gene definitively known to cause the disease." The evidence for this variant shows: no familial segregation data. 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 variation and where missense is a common mechanism of disease." The evidence for this variant shows: it is an in‐frame indel, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Protein: REVEL >.7333; RNA: At least one well‐established in silico predictor shows impact on splicing." The evidence for this variant shows: SpliceAI score is 0.03 (no predicted splicing impact) and no REVEL data. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotypic information provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "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: ClinVar entries are VUS, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Filtering Allele Frequency >.5%." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Filtering Allele Frequency >.05%." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant or fully penetrant disorder with no symptoms." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Use when a variant rescues both an ATM‐specific feature AND radiosensitivity (Moderate) or either feature (Supporting)." The evidence for this variant 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 family members." The evidence for this variant 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 for which primarily truncating variants are known to cause disease." The evidence for this variant shows: it is an in‐frame indel. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Use ATM PM3/BP2 table for observations in cis or in trans inconsistent with disease mechanism." The evidence for this variant shows: no relevant allelic data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in a repetitive region without a known functional role." The evidence for this variant shows: region context not repetitive. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Protein Analysis: Metapredictor REVEL score ≤.249; RNA: at least one well‐established in silico predictor (e.g. SpliceAI) shows no impact on splicing." The evidence for this variant shows: SpliceAI predicts no impact on splicing (max score 0.03). Therefore, this criterion is applied at Supporting strength.
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 for this variant shows: no alternate molecular diagnosis. 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 but evidence is not available." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing (for cDNA-level evidence)." The evidence for this variant shows: it is an in‐frame indel, not synonymous. Therefore, this criterion is not applied.