ATM c.497-6_497-4del, p.?
NM_000051.4:c.497-6_497-4del
Variant of Uncertain Significance (VUS)
This intronic ATM variant c.497-6_497-4delTTT is outside canonical splice sites, absent of functional or segregation data, and shows only a benign-supporting computational prediction (BP4). Population frequency exceeds the gene-specific PM2 threshold. No pathogenic criteria are met, yielding a final classification of VUS.
ACMG/AMP Criteria Applied
BP4
Genetic Information
Gene & Transcript Details
Gene
ATM
Transcript
NM_000051.4
MANE Select
Total Exons
63
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 63 exons | Forward |
Variant Details
HGVS Notation
NM_000051.4:c.497-6_497-4del
Protein Change
?
Location
Exon 5
(Exon 5 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.497-6_497-4del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00166%
Rare
Highest in Population
European (non-Finnish)
0.00413%
Rare
Global: 0.00166%
European (non-Finnish): 0.00413%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 60150Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00166%, 1/60150 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00413%, 1/24238 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Use ATM PVS1 Decision Tree". The evidence for this variant shows it is an intronic deletion outside the canonical ±1/2 splice sites (c.497-6_497-4). Therefore, this criterion is not applied because the variant does not affect canonical splice sites.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change, as long as splicing is ruled-out for both alterations." The evidence for this variant shows no known amino acid change. Therefore, this criterion is not applied because there is no matching pathogenic protein change.
PS2
PS2 (Not Applied) Strength Modified
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 no de novo data. Therefore, this criterion is not applied because parental origin data are unavailable.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Use ATM PS3 Decision Tree: Moderate when a variant fails to rescue both an ATM specific feature AND radiosensitivity; Supporting when it fails to rescue an ATM specific feature only." The evidence for this variant shows no functional studies. Therefore, this criterion is not applied because functional assay data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Case-control studies; p-value ≤ .05 AND (Odds ratio ≥2 OR lower 95% CI ≥1.5)." The evidence for this variant shows no case-control data. Therefore, this criterion is not applied because statistical association data are lacking.
PM1
PM1 (Not Applied) Strength Modified
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 it is intronic outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation." The evidence for this variant shows a MAF of 0.00166% (multiple alleles, multiple subpopulations). Therefore, this criterion is not applied because the allele frequency exceeds the gene-specific threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive disorders to evaluate variants in trans with a pathogenic variant." The evidence for this variant shows no trans observations in biallelic state. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants." The evidence for this variant shows an intronic deletion not altering protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; also for splice variants with high-quality observed splicing impact." The evidence for this variant shows no predicted truncation or high-quality splicing defect. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
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 no de novo assumption. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: REVEL >.7333; RNA: at least one in silico predictor shows impact on splicing." The evidence for this variant shows SpliceAI score 0.20 (below threshold) and no REVEL score. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
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 phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic." The evidence for this variant shows ClinVar lists it as VUS. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filtering Allele Frequency >.5%." The evidence for this variant shows MAF 0.00166%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Filtering Allele Frequency >.05%." The evidence for this variant shows MAF 0.00166%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." The evidence for this variant shows no such observation. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Moderate: Variant rescues both an ATM specific feature AND radiosensitivity; Supporting: rescues either." The evidence for this variant shows no functional rescue data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "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
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Strong/Moderate/Supporting: Use ATM PM3/BP2 table for cis observations." The evidence for this variant shows no cis observations with a pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows an intronic deletion outside repetitive sequence context. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: 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 minimal splicing impact (highest score 0.20, below threshold). Therefore, this criterion is applied at Supporting strength because computational evidence indicates no impact on splicing.
BP5
BP5 (Not Applied) Strength Modified
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 such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows ClinVar lists it as VUS. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous and deep intronic variants further than +7/−40 from splice sites." The evidence for this variant shows it lies at c.497-6_497-4, within the -40 to -3 window. Therefore, this criterion is not applied.