ATM c.4611+2T>C, p.Splice_Site
NM_000051.4:c.4611+2T>C
COSMIC ID: COSM6979040
Pathogenic
c.4611+2T>C affects a canonical splice donor site in ATM, is absent from population databases, and is predicted to disrupt splicing. Apply PVS1 Very Strong, PM2 Supporting, PP3 Supporting leading to a Pathogenic classification per ACMG/AMP and ATM-specific VCEP guidelines.
ACMG/AMP Criteria Applied
PVS1
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.4611+2T>C
Protein Change
Splice
Location
Exon 30
(Exon 30 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM6979040
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.4611+2T>C
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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: 4.55
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
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.4611+2T>C affects the canonical +2 splice donor site in ATM, predicted to abolish normal splicing in a gene where loss of function is a known mechanism; Therefore, this criterion is applied at Very Strong strength because the variant disrupts a canonical splice site per the ATM-specific 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: this is a splice site alteration, not a protein-level identical 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) in a patient with the disease and no family history of the disease"; The evidence for this variant shows: no de novo occurrence data are available; Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, "Moderate Strength: Moderate 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 assay data (e.g. kinase activity or splicing assays) are available; Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, "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 proband frequency data 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 (e.g., active site of an enzyme) without benign variation"; The evidence for this variant shows: c.4611+2T>C is a splice site variant, not within a defined protein domain; Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population"; The evidence for this variant shows: absent from population databases (gnomAD MAF=0%); Therefore, this criterion is applied at Supporting strength because the variant is extremely rare per ATM-specific frequency threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive diseases when detected in trans with a pathogenic variant; The evidence for this variant shows: no trans phasing data with another pathogenic ATM variant; Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, "PM4: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants"; The evidence for this variant shows: it is a splice site variant without defined in-frame coding change upstream of stop codon; 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 specific PTC location data relative to p.R3047 or high-quality splicing impact data; 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 assumed de novo data; 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"; The evidence for this variant shows: no family segregation data; 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"; The evidence for this variant shows: it is a splice site variant, not a missense; Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, "Supporting Strength: Supporting RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing"; The evidence for this variant shows: SpliceAI predicts donor loss score of 0.90 indicating significant splicing disruption; Therefore, this criterion is applied at Supporting strength because in silico predictors support a deleterious splicing 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 clinical data provided; 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"; The evidence for this variant shows: not found in ClinVar or other databases; Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, "Stand Alone Strength: Stand Alone Filtering Allele Frequency >.5%"; The evidence for this variant shows: allele frequency is 0%; Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, "Strong Strength: Strong Filtering Allele Frequency >.05%"; The evidence for this variant shows: allele frequency is 0%; Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, "BS2: Observed in healthy adult individuals for a recessive disease with full penetrance"; The evidence for this variant shows: no healthy carrier data; Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, "Supporting Strength: Supporting Use when a variant rescues EITHER an ATM specific feature OR radiosensitivity"; The evidence for this variant shows: no rescue functional 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: it is a splice site variant, not a missense; Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies when observed in cis with a pathogenic variant; The evidence for this variant shows: no cis phasing data; 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"; The evidence for this variant shows: not located in a repetitive region; Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, "BP4: Multiple lines of computational evidence suggest no impact"; The evidence for this variant shows: mixed computational results with high SpliceAI score indicating impact; Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, "BP5: Variant found in a case with an alternate molecular basis for disease"; The evidence for this variant shows: no alternate molecular basis reported; Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, "BP6: Reputable source reports variant as benign"; The evidence for this variant shows: no such report exists; Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, "BP7 applies to synonymous and deep intronic variants beyond ±7/−40 positions"; The evidence for this variant shows: this is a canonical splice site variant at +2; Therefore, this criterion is not applied.