ATM c.3153+1G>T, p.Splice_Site
NM_000051.4:c.3153+1G>T
Pathogenic
This canonical splice donor variant in ATM is absent from population databases, predicted by SpliceAI to abrogate normal splicing, and meets VCEP PVS1 (Very Strong), PM2 (Supporting), and PP3 (Supporting) criteria, supporting a Pathogenic classification.
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.3153+1G>T
Protein Change
Splice
Location
Exon 21
(Exon 21 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.3153+1G>T
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
1 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change affects a donor splice site in intron 21 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 953360). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (3 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: 6.50
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines for PVS1: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree". The evidence for this variant shows that c.3153+1G>T affects the canonical +1 splice donor site predicted to lead to aberrant splicing and NMD in a gene where loss-of-function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP ATM PVS1 decision tree for canonical splice site variants outside the last exon.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: "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 shows this is a splice site variant, not a protein‐level change with splicing ruled out. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no reported de novo observations. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3: "Do not use as strong. Use moderate when a variant fails to rescue both an ATM-specific feature and radiosensitivity." There are no functional studies characterizing this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS4: "Case-control studies; p-value ≤0.05 AND (Odds ratio ≥2 OR lower 95% CI ≥1.5)." No case-control data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM1: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." There is no evidence that this splice site lies in a defined hotspot or functional domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2: "Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation; n>1 would not apply." The variant is absent from gnomAD (frequency = 0%). Therefore, PM2 is applied at Supporting strength because it meets the VCEP rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines for PM3: "Use ATM PM3/BP2 table for recessive observations." There is no evidence of this variant in trans with another pathogenic ATM variant in an affected individual. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame deletions/insertions or stop-loss." This is a splice donor variant, not an in-frame indel or stop-loss. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: "Supporting Strength: frameshift/truncating variants upstream of p.R3047 with observed high-quality splicing impact and NMD prone." While this variant is predicted to truncate upstream of p.R3047, there is no high-quality observed RNA evidence. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM6: "Assumed de novo, but without confirmation of paternity and maternity." No such evidence is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP1: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." This is a splice site variant, not a missense. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines for PP3: "Supporting Strength: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing." SpliceAI predicts donor loss (score 0.93). Therefore, PP3 is applied at Supporting strength because the in silico evidence supports deleterious splicing impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP4: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No phenotype data specific to ATM disease are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP5: "Reputable source recently reports variant as pathogenic, but evidence is not available." ClinVar reports this variant as 'Likely pathogenic,' not 'Pathogenic.' Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: "Filtering allele frequency >.5% leads to stand-alone benign classification." The variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Filtering allele frequency >.05% is strong evidence for benign." The variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS2: "Observed in a healthy adult individual for a recessive (homozygous) variant." No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: "Use functional rescue data." No functional rescue data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines for BS4: "Lack of segregation in affected members." No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP1: "Missense variant in a gene where only loss-of-function causes disease." This is a loss-of-function splice variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP PM3/BP2 table guidance: "Evidence of observation in trans may support benign evaluation." There is no trans observation. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3: "In-frame deletions/insertions in repetitive regions." Not applicable to this splice site variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for BP4: "Supporting Strength: RNA: At least one predictor shows no impact on splicing." SpliceAI predicts a strong impact. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP5: "Variant found in a case with an alternate molecular basis for disease." No such evidence. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP6: "Reputable source reports as benign without underlying evidence." No benign reports exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP7: "Synonymous or deep intronic variants with no predicted impact on splicing." This is a canonical splice site variant. Therefore, BP7 is not applied.