ATM c.3030C>T, p.Asn1010=
NM_000051.4:c.3030C>T
Likely Benign
NM_000051.4:c.3030C>T is a synonymous variant with no predicted splicing impact, rare in population but above VCEP thresholds for PM2, and reported benign in ClinVar. It meets two Supporting benign criteria (BP6 and BP7), yielding a final classification of Likely Benign.
ACMG/AMP Criteria Applied
BP6
BP7
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.3030C>T
Protein Change
N1010=
Location
Exon 20
(Exon 20 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.3030C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
Admixed American
0.00289%
Rare
Global: 0.000398%
Admixed American: 0.00289%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251272Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251272 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00289%, 1/34580 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
4 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (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: 0.52
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 Use ATM PVS1 Decision Tree' which applies to predicted null variants. The evidence for this variant shows: NM_000051.4:c.3030C>T is a synonymous variant with no predicted impact on splicing. Therefore, this criterion is not applied because synonymous variants do not meet PVS1 null variant requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Use for protein changes as long as splicing is ruled-out.' The evidence for this variant shows: NM_000051.4:c.3030C>T does not change the amino acid (p.Asn1010=). Therefore, this criterion is not applied because there is no amino acid change to match a known pathogenic variant.
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 disease and no family history.' The evidence for this variant shows: no de novo or family segregation data are available. Therefore, this criterion is not applied because de novo status cannot be established.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Moderate Use when a variant fails to rescue both an ATM specific feature …' and 'Supporting Use when a variant fails to rescue an ATM specific feature only.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because no ATM‐specific functional data are available.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Case-control studies; p-value ≤ .05 AND OR ≥ 2 (or lower 95% CI ≥ 1.5).' The evidence for this variant shows: no case-control or statistical association data are available. Therefore, this criterion is not applied because no case-control evidence exists.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well‐studied functional domain without benign variation.' The evidence for this variant shows: c.3030C>T is a synonymous change outside known functional domains. Therefore, this criterion is not applied because the variant is not in a recognized hotspot or critical domain.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Frequency ≤ .001% if n=1 in a single subpopulation.' The evidence for this variant shows: although the overall MAF is 0.000398%, the Admixed American subpopulation frequency is 0.00289% (1/34580 alleles), exceeding the 0.001% threshold. Therefore, this criterion is not applied because the variant frequency in a subpopulation does not meet the VCEP rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive cases.' The evidence for this variant shows: no evidence of trans alleles in a recessive context. Therefore, this criterion is not applied because there is no PM3 table evidence.
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.' The evidence for this variant shows: c.3030C>T is synonymous with no length change. Therefore, this criterion is not applied because the protein length is unchanged.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Supporting for truncating variants with PTC upstream of p.R3047.' The evidence for this variant shows: it is synonymous and not truncating. Therefore, this criterion is not applied because PM5 does not apply to synonymous variants.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied because de novo status cannot be assumed.
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 family segregation data are available. Therefore, this criterion is not applied because segregation evidence is lacking.
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 variants.' The evidence for this variant shows: c.3030C>T is synonymous, not missense. Therefore, this criterion is not applied because PP2 is not applicable to synonymous changes.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting for REVEL > .7333 or RNA predictor shows impact on splicing.' The evidence for this variant shows: SpliceAI predicts no impact (max score 0.01) and REVEL is not elevated. Therefore, this criterion is not applied because computational evidence does not support a deleterious impact.
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 gene.' The evidence for this variant shows: no phenotype or family history data linking specifically to ATM deficiency. Therefore, this criterion is not applied because phenotypic specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' The evidence for this variant shows: ClinVar reports this variant as Likely Benign or Benign. Therefore, this criterion is not applied because no reputable source reports it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency > 5% in population databases.' The evidence for this variant shows: the highest MAF is 0.00289%, well below 5%. Therefore, this criterion is not applied because BA1 frequency threshold is not met.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: the maximum MAF of 0.00289% is below commonly used BS1 thresholds (e.g., >0.05%). Therefore, this criterion is not applied because allele frequency is not high enough.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals at inappropriate frequency.' The evidence for this variant shows: no homozygotes or direct healthy control observations are documented. Therefore, this criterion is not applied because BS2 cannot be established.
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 rescues one.' The evidence for this variant shows: no functional rescue studies are available. Therefore, this criterion is not applied because no rescue data exist.
BS4
BS4 (Not Applied) Strength Modified
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 are available. Therefore, this criterion is not applied because BS4 cannot be assessed.
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 cause disease.' The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied because BP1 pertains to missense variants.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for cis/trans observations.' The evidence for this variant shows: no evidence of cis/trans with pathogenic variants. Therefore, this criterion is not applied because BP2 cannot be established.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive region without known function.' The evidence for this variant shows: c.3030C>T is a single-nucleotide synonymous change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting for protein REVEL ≤ .249 or RNA predictor shows no impact; BP4 for splice predictions may not be applied with BP7.' The evidence for this variant shows: SpliceAI predicts no impact, but BP7 is applied for synonymous variants. Therefore, BP4 is not applied to avoid overlap with BP7.
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 alternate molecular basis is documented. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source recently reports variant as benign, but evidence not available to the laboratory.' The evidence for this variant shows: ClinVar lists NM_000051.4:c.3030C>T as Likely Benign (4 submissions) and Benign (1 submission). Therefore, this criterion is applied at Supporting strength because multiple reputable sources report benign status without primary evidence.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Can be considered for synonymous variants with no impact on splicing.' The evidence for this variant shows: SpliceAI predicts minimal impact (max score 0.01) and no new splice site is created. Therefore, this criterion is applied at Supporting strength because it is a synonymous change with no predicted splicing impact.