ATM c.3154-4G>T, p.?
NM_000051.4:c.3154-4G>T
Likely Benign
c.3154-4G>T in ATM is classified as Likely Benign based on two supporting benign criteria (BP4: multiple computational predictors show no splicing or protein impact; BP6: reputable source reports benign), with absence of other pathogenic evidence and allele frequency not meeting pathogenic thresholds.
ACMG/AMP Criteria Applied
BP4
BP6
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.3154-4G>T
Protein Change
?
Location
Exon 21
(Exon 21 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.3154-4G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00142%
Rare
Highest in Population
African/African American
0.00401%
Rare
Global: 0.00142%
African/African American: 0.00401%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282472Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00142%, 4/282472 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00401%, 1/24920 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
6 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (6 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: -0.18
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 (gene-specific)". The evidence for this variant shows: c.3154-4G>T is at position –4 relative to the exon and is outside the canonical ±1-2 splice sites. Therefore, this criterion is not applied because the variant does not meet the gene-specific PVS1 splice site requirements.
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." The evidence for this variant shows: c.3154-4G>T does not alter the protein sequence and there is no known identical amino acid change. 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 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 functional studies when a variant fails to rescue ATM-specific features AND radiosensitivity (Moderate) or fails to rescue an ATM-specific feature only (Supporting)." The evidence for this variant shows: no functional characterization studies exist for c.3154-4G>T. Therefore, this criterion is not applied due to absence of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Case-control data with significant association (OR ≥2 and p≤0.05)." The evidence for this variant shows: no case-control or statistical association data. 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 or well-established functional domain without benign variation." The evidence for this variant shows: c.3154-4G>T lies outside known functional domains/hot spots. 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." The evidence for this variant shows: global MAF=0.00142% (4/282 472 alleles, >1 allele in multiple subpopulations). Therefore, this criterion is not applied because the allele frequency exceeds the VCEP threshold for PM2_supporting.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Evidence of trans configuration with a pathogenic variant in recessive disorders." The evidence for this variant shows: no compound heterozygosity or trans data available. 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 or stop-loss variants." The evidence for this variant shows: c.3154-4G>T does not alter coding sequence length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5_supporting is: "Genomic frameshift/truncating variants with PTC upstream of p.R3047 or splice variants causing PTC with NMD." The evidence for this variant shows: c.3154-4G>T is an intronic variant without PTC generation. 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 without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. 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 low rate of benign missense variation and where missense is a common 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: "Supporting if protein REVEL>0.7333 or RNA: at least one predictor shows splicing impact." The evidence for this variant shows: SpliceAI maximum score 0.12 (below typical significance), CADD -0.18, indicating no deleterious effect. 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 phenotype data provided. 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 but evidence not available." The evidence for this variant shows: no reputable source reports pathogenicity. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency >0.5%." The evidence for this variant shows: global MAF=0.00142%, well below 0.5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Filtering allele frequency >0.05%." The evidence for this variant shows: global MAF=0.00142%, below 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 healthy adult individuals for a recessive condition." The evidence for this variant shows: no data on healthy adult observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Functional studies showing rescue of ATM-specific features (Moderate/Supporting)." 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 and not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Observation in trans with a pathogenic variant in an autosomal dominant disorder." The evidence for this variant shows: no trans observations. 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 repetitive regions without a known function." The evidence for this variant shows: it is an intronic SNV. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting if protein REVEL ≤0.249 OR RNA: at least one predictor shows no splicing impact." The evidence for this variant shows: SpliceAI score 0.12 (below significance), CADD -0.18 indicating no deleterious effect. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict no impact on splicing or protein function.
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 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Likely benign by six laboratories without accessible evidence. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or deep intronic variants >+7 or <−40 that have no predicted splice impact." The evidence for this variant shows: it is at –4, within the splicing region. Therefore, this criterion is not applied.