ATM c.9131A>G, p.Asn3044Ser
NM_000051.4:c.9131A>G
Variant of Uncertain Significance (VUS)
ATM c.9131A>G (N3044S) is absent from population databases (PM2_Supporting) and computational predictions strongly support deleterious effect (PP3_Supporting). No other supporting or contradicting evidence is present, resulting in classification as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP3
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.9131A>G
Protein Change
N3044S
Location
Exon 63
(Exon 63 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3044 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.9131A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 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 (2 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
No evidence of other pathogenic variants at position 3044 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.868
0.868
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.70primateai: T
Neutral: Show all
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 Modification Type: Gene-specific,Strength". The evidence for this variant shows: it is a missense change (N3044S) that does not introduce a null effect. Therefore, this criterion is not applied.
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 for both alterations". The evidence for this variant shows: no other established pathogenic variant produces the same amino acid change N3044S. 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: "Moderate Strength: 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 have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Strong 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 enrichment data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Use for variants located in critical functional domains or hotspots" (gene-specific). The evidence for this variant shows: N3044 is not located in a defined ATM hotspot or well‐characterized functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply". The evidence for this variant shows: it is absent from gnomAD and other control databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive inheritance". The evidence for this variant shows: no evidence of trans or cis compound heterozygosity. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Use for stop-loss variants". The evidence for this variant shows: it is a missense change, not a stop-loss or frameshift. 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". The evidence for this variant shows: it is a missense variant at N3044, with no other known pathogenic missense at this residue. 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 data are 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". The evidence for this variant shows: ATM tolerates missense changes and has known benign missense. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing". The evidence for this variant shows: a REVEL score of 0.87, exceeding 0.7333, and multiple damaging predictions. Therefore, this criterion is applied at Supporting strength.
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 specific 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 recently reports variant as pathogenic". The evidence for this variant shows: ClinVar asserts VUS only. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Filtering Allele Frequency >.5%". The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Filtering Allele Frequency >.05%". The evidence for this variant shows: absent from control databases. 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". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Moderate Strength: Use when a variant rescues both an ATM specific feature AND radiosensitivity". The evidence for this variant shows: no functional assays 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 studies. 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: ATM has pathogenic missense variants. 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". The evidence for this variant shows: no evidence of cis-trans relationships affecting pathogenicity. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions". The evidence for this variant shows: it is a single nucleotide substitution. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Protein Analysis: Metapredictor REVEL score ≤.249". The evidence for this variant shows: REVEL is 0.87, which exceeds the benign threshold. 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 diagnosis 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 as benign". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Use for synonymous and deep intronic variants". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.