NM_000051.4:c.662+13_662+14del is an intronic deletion in ATM at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus. SpliceAI predicts no significant splice impact (max delta score=0.05), indicating this variant is unlikely to disrupt normal ATM mRNA splicing.1 The variant is present at extremely low frequency in gnomAD v4.1 (2/1,613,430 alleles; AF=1.24e-06; 0.000124%), meeting ATM VCEP PM2_Supporting criteria (<=0.001%).2 The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and absent from ClinVar classifications.3 As an intronic variant beyond +7 with no predicted splice impact, BP7 (deep intronic, supporting) and BP4 (no predicted splicing impact, supporting) both apply per ATM VCEP v1.5.0.4 No functional studies (PS3/BS3), segregation data (PP1), case-control studies (PS4), or phase observations (PM3/BP2) are available for this variant.
ATM
Final classification
Likely Benign
ATM c.662+13_662+14del · p.?
ATM
NM_000051.4:c.662+13_662+14del is an intronic deletion in ATM at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; maps to Likely Benign.
Classification rationale
PM2
BP4BP7
Likely Benign
ATM c.662+13_662+14del
PM2 + BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 10 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
Per ATM VCEP v1.5.0, PM2_Supporting applies when frequency is <=0.001% in gnomAD v4. This variant is present at extremely low frequency in gnomAD v4.1 (AF=1.24e-06, 0.000124%, 2/1,613,430 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada. The frequency is well below the 0.001% threshold.
gnomAD v4.1: AF=1.24e-06 (0.000124%)2/1613
✓
BP4
supporting
Benign
Per ATM VCEP v1.5.0, BP4 for splicing applies when SpliceAI <=0.1, indicating no predicted impact via splicing. SpliceAI max delta score for this variant is 0.05, which falls below the 0.1 threshold. Multiple lines of computational evidence (SpliceAI) suggest no impact on splicing.
SpliceAI max delta score = 0.05 (<=0.1 threshold for BP4)
✓
BP7
supporting
Benign
Per ATM VCEP v1.5.0, BP7 applies to deep intronic variants defined as further than (but not including) +7 at donor sites. This variant is at position +13/+14 of the intron 6 donor site, which is beyond +7. SpliceAI predicts no significant splice impact (max delta=0.05). No aberrant RNA defect has been observed.
Variant located at +13/+14 of intron 6 donor site (deep intronicbeyond +7)SpliceAI max delta score = 0.05 (no predicted splice impact)
Assessed · not applied
Pathogenic
PVS1
NM_000051.4:c.662+13_662+14del is an intronic deletion at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus.
PS1
Per the ATM VCEP v1.5.0 PS1 splicing table, PS1 requires a known pathogenic or likely pathogenic reference variant at the same nucleotide position with similar or stronger computational prediction of the same splicing outcome.
PS3
Per ATM VCEP v1.5.0, PS3 requires functional studies demonstrating a damaging effect on ATM-specific features (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity rescue failure.
PS4
Per ATM VCEP v1.5.0, PS4_Strong requires case-control studies with p-value <=0.05 and OR/HR/RR >=2 or lower 95% CI >=1.5.
PP1
Per ATM VCEP v1.5.0, PP1 for autosomal recessive conditions requires co-segregation in affected relatives with both variants identified in the proband.
PP3
Per ATM VCEP v1.5.0, PP3 for splicing requires SpliceAI >=0.2 for intronic variants outside donor/acceptor +/-1,2 sites.
Benign
BA1
Per ATM VCEP v1.5.0, BA1 requires Grpmax Filtering AF >0.5% in gnomAD v4.
BS1
Per ATM VCEP v1.5.0, BS1 requires Grpmax Filtering AF >0.05% in gnomAD v4.
BS3
Per ATM VCEP v1.5.0, BS3 requires functional studies showing rescue of ATM-specific features and/or radiosensitivity.
BP2
Per ATM VCEP v1.5.0, BP2 requires observation of the variant in cis with a pathogenic ATM variant, or in trans with a P/LP variant in an unaffected individual aged 18+ without evidence of A-T.
N/A · 14
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.2396e-06; MAF= 0.00012%, 2/1613430 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33558e-05; MAF= 0.00134%, 1/74874 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,613,430
0 hom
0 hom
African/African American 1 / 74,874 |
0.0013% |
European (non-Finnish) 1 / 1,179,730 |
8.5e-05% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
24418350 ↗
EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR