ATM c.6006+13G>C, p.?
NM_000051.4:c.6006+13G>C
Likely Benign
This deep intronic ATM variant is absent from canonical splice regions and functional domains, shows no predicted splicing or protein impact (BP4), is reported as likely benign in ClinVar (BP6), and qualifies as deep intronic beyond +7 (BP7). With three supporting benign criteria and no evidence of pathogenicity, the variant is classified as Likely Benign.
ACMG/AMP Criteria Applied
BP4
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.6006+13G>C
Protein Change
?
Location
Exon 40
(Exon 40 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.6006+13G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00248%
Rare
Highest in Population
European (non-Finnish)
0.00544%
Rare
Global: 0.00248%
European (non-Finnish): 0.00544%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281860Alt: 7Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00248%, 7/281860 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00544%, 7/128754 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 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 (4 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: -0.08
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: c.6006+13G>C is located outside the canonical splice site (+1/+2) and is intronic. Therefore, this criterion is not applied because the variant is not predicted to result in loss-of-function per the ATM PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Strong 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: no amino acid change is produced (intronic), and splicing impact is predicted to be negligible. Therefore, this criterion is not applied because there is no protein-altering change to compare.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS2: Confirmed de novo in a patient with the disease and no family history of the disease.". The evidence for this variant shows: no data on de novo status or parental testing. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Strong Do not use as strong. Modification Type: Gene-specific". The evidence for this variant shows: no functional studies assessing ATM-specific feature rescue or radiosensitivity. Therefore, this criterion is not applied because functional evidence is absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS4: Case-control studies with p-value ≤0.05 AND (Odds ratio ≥2.0 or lower 95% CI ≥1.5).". The evidence for this variant shows: no case-control or proband frequency data. Therefore, this criterion is not applied due to lack of statistical evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM1: Located in a mutational hot spot or critical and well-established functional domain without benign variation.". The evidence for this variant shows: no evidence that c.6006+13G>C lies in a known hot spot or functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. 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=0.00248% (7/281,860 alleles) across multiple populations. Therefore, this criterion is not applied because the variant frequency exceeds the VCEP threshold for PM2_supporting.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Supporting Use ATM PM3/BP2 table". The evidence for this variant shows: no data on trans observations in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Strength: Moderate Use for stop-loss variants.". The evidence for this variant shows: no stop-loss or protein length change is predicted. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047...". The evidence for this variant shows: no frameshift or truncating effect. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM6: Assumed de novo, but without confirmation of paternity and maternity.". The evidence for this variant shows: no parental inheritance information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP1: Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP2: Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.". The evidence for this variant shows: intronic change with no missense effect. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing.". The evidence for this variant shows: SpliceAI score=0.08 predicting minimal splicing disruption. Therefore, this criterion is not applied because computational evidence does not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP4: 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 or family history data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: reputable sources report it as benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "Stand Alone Strength: Filtering Allele Frequency >.5%.". The evidence for this variant shows: MAF=0.00248%, below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Filtering Allele Frequency >.05%.". The evidence for this variant shows: MAF=0.00544% (European non-Finnish), below the BS1 threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BS2: Observed in a healthy adult individual for a recessive (homozygous) disorder.". The evidence for this variant shows: no data on homozygous observations in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Strength: Moderate Use when a variant rescues both an ATM specific feature and radiosensitivity.". 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: "BS4: 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: "BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease.". The evidence for this variant shows: intronic change, no missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Supporting Use ATM PM3/BP2 table". The evidence for this variant shows: no cis/trans data with other pathogenic variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP3: In-frame deletions/insertions in a repetitive region without a known function.". The evidence for this variant shows: no indication it lies in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines: "Supporting Strength: Supporting 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 no splicing impact (score 0.08) and CADD score -0.08 suggests no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence indicates a benign outcome.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP5: Variant found in a case with an alternate molecular basis for the disease.". The evidence for this variant shows: no such case reported. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines: "BP6: Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar reports it as Likely benign by four clinical laboratories. Therefore, this criterion is applied at Supporting strength because multiple reputable sources classify it as benign without accessible evidence.
BP7
BP7 (Supporting)
According to VCEP guidelines: "Supporting Strength: Supporting Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than +7 at donor and further than -40 at acceptor sites.". The evidence for this variant shows: c.6006+13G>C is 13 nucleotides into the intron (beyond +7). Therefore, this criterion is applied at Supporting strength because it qualifies as a deep intronic variant without predicted splicing impact.