ATM c.7516-9del, p.?
NM_000051.4:c.7516-9del
COSMIC ID: COSN26967155, COSN26967157
Likely Benign
NM_000051.4:c.7516-9delT is a rare intronic variant with no predicted splice impact (SpliceAI 0.04), no functional data, and is reported as benign in ClinVar. Only BP4 and BP6 apply, yielding a Likely Benign classification under ACMG guidelines.
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.7516-9del
Protein Change
?
Location
Exon 50
(Exon 50 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN26967155, COSN26967157
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.7516-9del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00743%
Rare
Highest in Population
South Asian
0.0255%
Low Frequency
Global: 0.00743%
South Asian: 0.0255%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 228758Alt: 17Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00743%, 17/228758 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.0255%, 7/27502 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
3 LB
2 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 (3 clinical laboratories) and as Benign (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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: "PVS1: Very Strong Use ATM PVS1 Decision Tree". The variant is intronic at position -9, outside the canonical ±1–2 splice sites with no evidence of aberrant splicing. Therefore, this criterion is not applied because the variant does not meet the gene-specific PVS1 decision tree for loss-of-function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "PS1: Strong Use for protein changes as long as splicing is ruled-out for both alterations." The variant is intronic with no amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS2: De novo (both maternity and paternity confirmed)." No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: "PS3: Strong/Moderate/Supporting strength for functional studies of ATM-specific assays." No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "PS4: Strong Case-control studies; p-value ≤.05 AND (OR ≥2)." No case-control or proband frequency data meeting VCEP thresholds are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM1: Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The variant is intronic, not within a known hotspot or functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines: "PM2: Supporting Strength: Frequency ≤.001% if n=1 in a single sub population." The variant MAF is 0.00743% in gnomAD (17/228,758 alleles, n>1). Therefore, this criterion is not applied because it does not meet the gene-specific rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "PM3: Gene-specific rules for recessive trans observations." No evidence of trans observations with a pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM4: Protein length changes as a result of in-frame deletions/insertions in a non-repeat region." The variant is intronic. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "PM5: Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The variant is intronic. 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." No de novo data are available. 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." No segregation data are 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 low rate of benign missense variation." The variant is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "PP3: Supporting for REVEL >.7333 or RNA splicing predictor shows impact." SpliceAI score is 0.04, indicating no significant splicing impact, and REVEL is not applicable. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP4: Patient’s phenotype or family history specifically supports a genetic etiology." No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic but evidence not available." The variant is reported as benign/likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "BA1: Stand Alone Filtering Allele Frequency >.5%." The variant MAF is 0.00743% < 0.5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "BS1: Strong Filtering Allele Frequency >.05%." The variant MAF is 0.00743% < 0.05%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BS2: Observed in a healthy adult with full penetrance expected at an early age." No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "BS3: Functional studies show no damaging effect." No functional rescue data are available. 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." 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 where only truncating variants cause disease." The variant is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "BP2: Observed in trans with a pathogenic variant in a recessive disorder." No such data are available. 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 variant is intronic. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines: "BP4: Multiple lines of computational evidence suggest no impact on gene or gene product." SpliceAI predicts no impact on splicing (max score 0.04) and no other in silico tools suggest deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports no splicing or functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP5: Variant found in a case with an alternate molecular basis for disease." No such case data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines: "BP6: Reputable source reports variant as benign, but evidence is not available to the laboratory to perform an independent evaluation." ClinVar entries (3 labs Likely benign, 2 labs Benign) support benign classification but underlying evidence is unavailable. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP7: Synonymous or deep intronic variant with no predicted splicing impact located beyond ±7/−40 intronic positions." This variant is at −9, within the intronic region where splice effects cannot be excluded by default. Therefore, this criterion is not applied.