ATM c.8988-27C>G, p.?
NM_000051.4:c.8988-27C>G
Variant of Uncertain Significance (VUS)
This deep intronic ATM variant is rare but lacks splicing, functional, segregation or phenotypic evidence to support impact and therefore remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
No ACMG/AMP criteria definitively applied.
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.8988-27C>G
Protein Change
?
Location
Exon 62
(Exon 62 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.8988-27C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00199%
Rare
Highest in Population
Remaining individuals
0.0163%
Low Frequency
Global: 0.00199%
Remaining individuals: 0.0163%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251286Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00199%, 5/251286 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0163%, 1/6126 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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.33
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: 'Use ATM PVS1 Decision Tree'. The evidence for this variant shows: it is a deep intronic variant at c.8988-27C>G not affecting canonical ±1 or ±2 splice sites. Therefore, this criterion is not applied because the variant does not meet any PVS1 categories in the ATM decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: '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 for this variant shows: there is no amino acid change and no match to a known pathogenic amino acid substitution. Therefore, this criterion is not applied.
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 segregation data are available. Therefore, this criterion is not applied.
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 characterization in ATM-specific assays is available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control data).' The evidence for this variant shows: no case-control or large cohort data are available. Therefore, this criterion is not applied.
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 a deep intronic variant outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2_supporting is: 'Frequency ≤0.001% if n=1 in a single subpopulation; n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply.' The evidence for this variant shows: MAF=0.00199% (5/251286 alleles), n>1. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for evidence of variants in trans with a pathogenic variant in recessive disease.' The evidence for this variant shows: no data on phase with another pathogenic ATM variant. 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: it is intronic with no predicted protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; can apply supporting for splice variants with PTC upstream of p.Arg3047 when PVS1_VS(RNA) applied.' The evidence for this variant shows: it is a deep intronic substitution without frameshift or PTC. 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 data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data are available. 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 low rate of benign missense variation and where missense is a common disease mechanism.' The evidence for this variant shows: it is intronic and not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Protein: REVEL >0.7333; RNA: at least one well-established in silico predictor shows impact on splicing.' The evidence for this variant shows: CADD score low (1.33) and SpliceAI maximum 0.26 (below typical thresholds). 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 highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no specific phenotype correlation reported. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without available evidence.' The evidence for this variant shows: ClinVar reports 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 >0.5%.' The evidence for this variant shows: MAF=0.00199% <0.5%. 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 >0.05%.' The evidence for this variant shows: MAF=0.00199% <0.05%. 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 expected at an early age.' The evidence for this variant shows: no data in healthy adults. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Moderate when a variant rescues both an ATM-specific feature and radiosensitivity; Supporting when it rescues either.' The evidence for this variant shows: no functional data demonstrating rescue. 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 for which primarily truncating variants are known to 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: 'Use ATM PM3/BP2 table for evidence of variants in cis with a pathogenic variant.' The evidence for this variant shows: no phase data. 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: it is a single nucleotide substitution in a non-repetitive intronic region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting when computational evidence suggests no impact (REVEL ≤0.249; RNA: at least one predictor shows no splicing impact).' The evidence for this variant shows: mixed in silico predictions and SpliceAI below, but insufficient to conclusively support benign computational evidence. Therefore, this criterion is not applied.
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 alternate molecular cause reported. 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 without evidence.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous or deep intronic variants >40 bp from exon boundaries with no predicted impact on splicing.' The evidence for this variant shows: it is located at –27, which is within 40 bp of the exon. Therefore, this criterion is not applied.