ATM c.4777-13T>A, p.?
NM_000051.4:c.4777-13T>A
Variant of Uncertain Significance (VUS)
This intronic ATM variant at c.4777-13T>A is classified as VUS. Only computational evidence (BP4) supports benign impact; no other pathogenic or benign criteria are met. Insufficient evidence precludes reclassification.
ACMG/AMP Criteria Applied
BP4
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.4777-13T>A
Protein Change
?
Location
Exon 31
(Exon 31 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.4777-13T>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00159%
Rare
Highest in Population
African/African American
0.0246%
Low Frequency
Global: 0.00159%
African/African American: 0.0246%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251160Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00159%, 4/251160 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0246%, 4/16242 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
4 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Clinical Statement
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (1 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: 1.07
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 an intronic change at position -13, outside the +1/+2 canonical splice sites. Therefore, this criterion is not applied because the variant does not meet the requirement for a null (loss-of-function) variant at canonical splice sites.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "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 and no known protein consequence. Therefore, this criterion is not applied because there is no established pathogenic protein change to compare.
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 data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP gene-specific guidelines for PS3, functional assays must show failure to rescue ATM-specific features. The evidence for this variant shows no functional study results. Therefore, this criterion is not applied because functional data are absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Case-control studies; p-value ≤ .05 AND (Odds ratio ≥2 or lower 95% CI ≥1.5)." The evidence for this variant shows no case-control or statistical association data. Therefore, this criterion is not applied due to lack of case-control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hotspot and/or critical and well-established functional domain." The evidence for this variant shows it is intronic and not within a characterized hotspot or domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Frequency ≤.001% if n=1 in a single sub-population." The evidence for this variant shows MAF=0.00159% with n=4 in gnomAD. Therefore, this criterion is not applied because the allele frequency and counts exceed the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive inheritance evidence." The evidence for this variant shows no data on trans configuration or recessive inheritance. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss." The evidence for this variant shows no change in coding sequence. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Use for novel missense at an amino acid residue where a different missense is pathogenic." The evidence for this variant shows no amino acid change. 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 without confirmation of paternity/maternity." The evidence for this variant shows no de novo information. 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. 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 and where missense is a common mechanism." The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting if protein REVEL >.7333; RNA: at least one predictor shows impact on splicing." The evidence for this variant shows SpliceAI score 0.12 (below threshold) and no REVEL data. Therefore, this criterion is not applied.
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 phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is deprecated and not recommended. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering Allele Frequency >.5%." The evidence for this variant shows MAF=0.00159%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Filtering Allele Frequency >.05%." The evidence for this variant shows MAF=0.00159%. 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 dominant disorder with full penetrance." 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: "Use when a variant rescues ATM-specific features in functional assays." The evidence for this variant shows no functional assay data. 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 data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense in gene where only loss-of-function is known mechanism." The evidence for this variant shows it is intronic. 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 for occurrence in trans with a pathogenic variant." The evidence for this variant shows no trans data. 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 region without a known function." The evidence for this variant shows no indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Protein Analysis: REVEL ≤.249; RNA: at least one predictor shows no impact on splicing." The evidence for this variant shows SpliceAI score 0.12, indicating minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence supports no splicing effect.
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 such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is deprecated and not recommended. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or deep intronic (>+7 or <-40) with no splicing impact." The evidence for this variant shows it is at -13, not in the deep intronic region. Therefore, this criterion is not applied.