ATM c.6975+13dup, p.?

Reasoning

ATM c.6975+13dupT is non-missense and intronic, so the VCEP splicing sub-path is the applicable BP4 mechanism. Its SpliceAI maximum delta of 0.007 is <=0.1; BP4 Supporting is met. The local missense-only BP4 override does not change this outcome.

Rule

ATM HBOP VCEP v1.5 BP4 Supporting, splicing sub-path: no predicted impact via splicing (SpliceAI <=0.1).

Evidence considered

• The ATM HBOP VCEP v1.5 BP4 splicing rule is no predicted splice impact at SpliceAI <=0.1.
• SpliceAI reports maximum delta 0.007, which is below the VCEP BP4 threshold of 0.1.
• The local BP4 override restricts missense variants to REVEL; this intronic variant remains eligible for the VCEP splicing sub-path.

Sources

Reasoning

The ATM HBOP VCEP specifies BP7 Supporting for deep intronic variants further than +7 at donor sites or further than -21 at acceptor sites. c.6975+13dupT is +13 and therefore meets the deep-intronic positional definition. BP7 is assigned from this VCEP positional rule, not from the SpliceAI prediction already used for BP4.

Rule

ATM HBOP VCEP v1.5 BP7 Supporting: synonymous and deep intronic variants further than +7 at donor sites or further than -21 at acceptor sites.

Evidence considered

• The submitted HGVS is NM_000051.4:c.6975+13dupT, placing the variant 13 bases into the intron following the donor site.
• The ATM HBOP VCEP v1.5 BP7 rule permits BP7 for deep intronic variants further than, but not including, +7 at donor sites and further than, but not including, -21 at acceptor sites.
• BP7 is based solely on the VCEP deep-intronic positional eligibility rule and does not duplicate the SpliceAI-based BP4 evidence.

Sources

Reasoning

ATM loss of function is an established disease mechanism, but NM_000051.4:c.6975+13dup is a non-canonical intronic duplication, 13 bases from the donor boundary. It is not a null-variant class covered by the ATM PVS1 guide, and SpliceAI predicts no significant splice impact (maximum delta 0.007); therefore a loss-of-function consequence and NMD are not supported.

Rule

ATM VCEP v1.5 PVS1 decision guide: apply PVS1 to qualifying null variants in ATM; this non-canonical intronic variant does not meet a qualifying null-variant path.

Evidence considered

• The ATM VCEP framework establishes loss of function as a disease mechanism and directs PVS1 assessment to the ATM PVS1 decision guide.
• The ATM PVS1 guide applies to null variants including nonsense, frameshift, canonical ±1/2 splice-site, initiation-codon, and exon-deletion variants; the assessed duplication at c.6975+13 is outside the canonical splice dinucleotide.
• SpliceAI maximum delta is 0.007, reported as no significant predicted splice impact. No RNA evidence or predicted aberrant transcript supports a premature termination codon or NMD.

Sources

Reasoning

The ATM VCEP v1.5 PM2 threshold is frequency <=0.001% in gnomAD v4.1, with PM2 Supporting assigned when the threshold is satisfied. The variant is present at total AF 0.000101939 (0.01019%) and has grpmax FAF 0.00032389 (0.032389%), both above 0.001%; therefore PM2 is not met. No homozygotes are observed, but absence of homozygotes does not overcome the allele-frequency threshold.

Rule

Frequency <=0.001% in gnomAD v4 dataset; if n=1 in a single subpopulation, that is sufficiently rare and PM2 Supporting would apply

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies PM2 Supporting for frequency <=0.001% in gnomAD v4.1 and notes that n=1 in a single subpopulation can qualify when sufficiently rare.
• gnomAD v4.1 reports 164/1,608,806 alleles, total AF 0.000101939 (0.01019%), grpmax FAF 0.00032389 (0.032389%), and zero homozygotes; the observed frequency is above the PM2 threshold.

Sources

Reasoning

The ClinGen HBOP ATM VCEP v1.5 PM3 specification applies a population-frequency eligibility limit: the variant may not exceed 0.01% in the general population. This variant has a gnomAD v4.1 group maximum filtering allele frequency of 0.00032389 (0.032389%), which exceeds that limit. The case bundle also contains no affected A-T proband observation, phase determination, or documented pathogenic/likely pathogenic ATM variant in trans that could otherwise contribute PM3 points.

Rule

ClinGen HBOP ATM VCEP v1.5 PM3: variant frequency must not exceed 0.01%; otherwise PM3 cannot be applied. If eligible, score unrelated A-T probands using the ATM PM3/BP2 points table: 1 point Supporting, 2 Moderate, 4 Strong, and 8 Very Strong.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 requires the variant to remain at or below 0.01% general-population frequency for PM3 and assigns PM3 strength from accumulated points per unrelated A-T proband.
• gnomAD v4.1 reports a group maximum filtering allele frequency of 0.00032389 (0.032389%), exceeding the ATM VCEP PM3 eligibility limit.
• The consolidated case-evidence bundle contains no documented affected A-T proband, phase result, or VCEP-classified pathogenic/likely pathogenic ATM variant in trans for this variant.

Still missing

• No affected A-T proband-level observations with this variant were provided.
• No parental or offspring testing establishing trans or cis phase was provided.
• No co-occurring ATM pathogenic/likely pathogenic variant classified under the ATM VCEP specifications was provided.

Sources

Reasoning

NM_000051.4:c.6975+13dup is an intronic duplication with no established protein consequence and is not a stop-loss variant. The ATM VCEP specification restricts PM4 to stop-loss variants.

Rule

ATM VCEP v1.5 PM4: Use for stop-loss variants.

Evidence considered

• The normalized consequence is NP_000042.3:p.?, consistent with an intronic variant without a demonstrated protein-length change.
• ATM VCEP v1.5 specifies PM4 for stop-loss variants only.

Sources

Reasoning

The ATM VCEP v1.5 PM5 rule is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and to splice variants with high-quality observed splicing impact, application of PVS1_VS(RNA), and NMD-prone consequence. This c.6975+13dup intronic variant has no observed RNA result or PVS1_VS(RNA) assessment, and SpliceAI predicts no significant splice impact (maximum delta 0.007). Therefore the VCEP PM5 rule is not satisfied.

Rule

ATM VCEP v1.5 PM5: apply at Supporting strength to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with high-quality observed splicing impact, PVS1_VS(RNA), and an NMD-prone consequence.

Evidence considered

• The ATM VCEP v1.5 PM5 rule applies to truncating or frameshifting variants upstream of p.Arg3047, or to splice variants only when high-quality observed splicing impact supports PVS1_VS(RNA) and the consequence is NMD-prone.
• The case classifies NM_000051.4:c.6975+13dup as an intronic variant with no predicted protein consequence and no PVS1 variant assessment applied.
• SpliceAI reports a maximum delta score of 0.007, providing no significant predicted splice impact.

Sources

Reasoning

ATM c.6975+13dupT is a non-canonical intronic variant. The ATM HBOP VCEP specifies PP3 Supporting for predicted splice impact with SpliceAI >=0.2; the observed maximum delta is 0.007, below that threshold.

Rule

ATM HBOP VCEP v1.5 PP3 Supporting: predicted splicing impact (SpliceAI >=0.2) for intronic variants outside donor and acceptor ±1,2 sites.

Evidence considered

• The ATM HBOP VCEP v1.5 PP3 splicing rule applies to intronic variants outside donor/acceptor ±1,2 positions when SpliceAI is >=0.2.
• SpliceAI reports DS_AG 0.007, DS_AL 0.000, DS_DG 0.001, and DS_DL 0.006; maximum delta 0.007.

Sources

Reasoning

The ATM VCEP v1.5 BA1 threshold is grpmax filtering AF >0.5% in gnomAD v4.1. This variant has a gnomAD v4.1 grpmax FAF of 0.00032389 (0.032389%), well below 0.5%; therefore BA1 is not met.

Rule

Grpmax Filtering AF >0.5% in gnomAD v4 dataset

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies BA1 as grpmax filtering AF >0.5% in gnomAD v4.1.
• gnomAD v4.1 reports total AF 0.000101939 (0.01019%), grpmax FAF 0.00032389 (0.032389%), and the highest named subpopulation AF 0.000881715 (0.08817%); none reaches the BA1 threshold.

Sources

Reasoning

The ATM VCEP v1.5 BS1 threshold is grpmax filtering AF >0.05% in gnomAD v4.1. The variant's gnomAD v4.1 grpmax FAF is 0.00032389 (0.032389%), below 0.05%; therefore BS1 is not met. The highest individual subpopulation AF is not the VCEP's specified grpmax metric and does not override the rule.

Rule

Grpmax Filtering AF >0.05% in gnomAD v4 dataset

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies BS1 as grpmax filtering AF >0.05% in gnomAD v4.1.
• gnomAD v4.1 reports grpmax FAF 0.00032389 (0.032389%), below the BS1 cutoff; total AF is 0.000101939 (0.01019%).

Sources

Reasoning

The variant is NM_000051.4:c.6975+13dup, an intronic variant with no predicted protein consequence (NP_000042.3:p.?). The ATM VCEP PS1 splice-region pathway requires a known P/LP reference variant at the same nucleotide or within the same donor/acceptor motif, plus a precisely matching predicted splice event and prediction strength that is equal to or greater than the reference. No qualifying reference variant, matched splice event, or VCEP-classified comparator is available in the case evidence. The standard missense PS1 pathway is not applicable because this variant has no missense consequence.

Rule

ATM VCEP v1.5 PS1: use for missense changes only when splicing is ruled out for both alterations; for splice variants, use the ATM PS1 splicing table and require a precisely matching predicted event and comparable or stronger prediction for the variant under assessment.

Evidence considered

• The case normalization reports NM_000051.4:c.6975+13dup with predicted protein consequence NP_000042.3:p.?.
• The ATM VCEP v1.5 PS1 specification permits standard PS1 for the same amino-acid change when splicing is ruled out, or splice-region PS1 only when the variant under assessment and a known P/LP reference have precisely matching predicted splice events and adequate relative prediction strength.
• SpliceAI reports a maximum delta score of 0.007 for this variant, but no qualifying P/LP reference variant with a matched splice event is provided.

Still missing

• A VCEP-classified P/LP ATM splice variant at the same nucleotide or within the same donor/acceptor motif is not available.
• A directly comparable predicted or experimentally observed splice event for the variant and reference is not available.

Sources

Reasoning

No variant-specific functional assay result was identified for ATM NM_000051.4:c.6975+13dupT. The applicable ATM VCEP v1.5 specification permits PS3 only when the variant fails to rescue an ATM-specific feature, with Supporting for failure of an ATM-specific feature alone and Moderate for failure of both an ATM-specific feature and radiosensitivity; it expressly prohibits Strong PS3. The VCEP-approved assay table is a methodology and calibration resource, not a per-variant result table, and the three approved kinase-activity papers and approved radiosensitivity assay do not appear in the case's fetched literature or paper-extract records for this variant. The available Sun et al. dataset is restricted to single-nucleotide variants and does not provide a directly measured result for this intronic duplication. Therefore PS3 cannot be assigned.

Rule

ATM VCEP v1.5 PS3: Supporting when the variant fails to rescue an ATM-specific feature only; Moderate when it fails to rescue both an ATM-specific feature and radiosensitivity; do not use Strong.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 states that PS3 must not be used as Strong; PS3_Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity, while PS3_Supporting requires failure to rescue an ATM-specific feature and must not be based on radiosensitivity alone.
• The VCEP-approved functional-assay resource describes approved ATM kinase-activity assays and calibrated strengths, but explicitly states that it is not a per-variant results table and requires confirmation that the assessed variant was tested in the cited paper.
• The case contains no paper-extract entry for the VCEP-cited functional assay PMIDs 18634022, 19431188, or 11805335, and no fetched source reports a result for NM_000051.4:c.6975+13dupT.
• Sun et al. Table S1 is described as a saturation single-nucleotide-variant dataset; the assessed variant is an intronic duplication, and no directly measured variant-specific result for it is present in the case evidence.

Still missing

• A primary publication or validated laboratory report showing this exact variant was experimentally tested is absent.
• No variant-specific ATM kinase/substrate phosphorylation result is available.
• No variant-specific validated radiosensitivity result is available; in the ATM VCEP, radiosensitivity cannot receive weight alone and must be interpreted with kinase activity.
• Assay controls, replicate structure, quantitative readout, and comparison with normal and ATM-null controls for this exact variant are unavailable.

Sources

Reasoning

The ATM HBOP VCEP permits PS4 at strong strength only for a case-control study with p<=0.05 and OR, HR, or RR >=2 (or lower 95% CI >=1.5). No exact-variant case-control dataset, effect estimate, confidence interval, or p-value was supplied. The reviewed candidate publications do not provide observations of NM_000051.4:c.6975+13dup.

Rule

ATM HBOP VCEP v1.5: Case-control studies; p-value <=0.05 AND (odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5).

Evidence considered

• ATM HBOP VCEP v1.5 PS4 rule: case-control studies require p<=0.05 and OR, HR, or RR >=2, or a lower 95% CI >=1.5; PS4_Moderate proband counting is not to be used.
• PMID:17508274 was selectively reviewed through its precomputed extraction; the exact ATM variant was not mentioned.
• PMID:18163131 was selectively reviewed through its precomputed extraction; the exact ATM variant was not mentioned.
• PMID:24418350 was selectively reviewed because no precomputed extraction was present; the full text contains no ATM or c.6975+13dup mention and is an adult chronic-ataxia diagnostic guideline rather than an exact-variant association study.

Still missing

• An exact-variant case-control analysis with affected and control allele counts, effect estimate, 95% confidence interval, and p-value is required.

Sources

Reasoning

PP1 is applicable for the ATM autosomal recessive condition only when an affected relative has both variants identified in the proband and the variant segregates with disease. The ATM VCEP calibrates strength as Supporting for one affected relative, Moderate for two, and Strong for at least three. The case-evidence bundle provides no affected relatives, family pedigree, segregation results, parental phase, meioses, or phenotype-linked testing for this variant; consequently, no PP1 strength can be assigned.

Rule

AR condition: affected relatives must have both variants identified in the proband; Supporting for segregation in 1 affected relative, Moderate for 2 affected relatives, and Strong for at least 3 affected relatives.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 states that PP1 is applicable for AR disease only when affected relatives have both variants identified in the proband.
• ClinGen HBOP ATM VCEP v1.5 assigns PP1 Supporting for segregation in one affected relative, Moderate for two affected relatives, and Strong for at least three affected relatives.
• The consolidated case-evidence bundle contains no case-specific segregation, affected-relative, parental-phase, or meiosis data.

Still missing

• Documented affected relatives with phenotype consistent with the relevant ATM autosomal recessive condition.
• Variant testing results in each affected relative and confirmation that both proband variants are identified where required.
• Pedigree, parental phase, and informative meioses sufficient to establish segregation.
• Clinical records supporting that the relatives' phenotype is attributable to the relevant ATM condition rather than a phenocopy or another cause.

Sources

Reasoning

No variant-specific functional result demonstrating normal ATM function was identified for ATM NM_000051.4:c.6975+13dupT. Under the ATM VCEP v1.5 specification, BS3_Supporting requires rescue of either an ATM-specific feature or radiosensitivity, and BS3_Moderate requires rescue of both; the approved-assay resource is only a methodology/strength calibration table and does not establish that this variant was tested. The case provides no qualifying kinase-activity or radiosensitivity result for the exact intronic duplication. The available Sun et al. resource concerns single-nucleotide variants and does not supply a directly measured result for this duplication. Therefore BS3 cannot be assigned.

Rule

ATM VCEP v1.5 BS3: Supporting when the variant rescues either an ATM-specific feature or radiosensitivity; Moderate when it rescues both.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 states that BS3_Supporting may be used when a variant rescues either an ATM-specific feature or radiosensitivity, and BS3_Moderate when it rescues both.
• The VCEP-approved functional-assay resource describes the required ATM kinase-activity and radiosensitivity methodologies and controls, but explicitly warns that the table is not a per-variant results table and cannot be used unless the assessed variant is confirmed in the cited paper.
• No case source reports normal functional rescue for NM_000051.4:c.6975+13dupT, and the case's paper-extract records do not contain a variant-specific functional assay publication.
• Sun et al. Table S1 is a single-nucleotide-variant resource and does not provide a directly measured functional result for this intronic duplication.

Still missing

• A primary publication or validated laboratory report showing this exact variant was experimentally tested is absent.
• No variant-specific normal ATM-specific feature, such as substrate phosphorylation, is available.
• No variant-specific validated radiosensitivity result is available.
• Assay controls, replicates, quantitative readout, and demonstration of rescue relative to ATM-null and wild-type controls for this exact variant are unavailable.

Sources

Reasoning

The ClinGen HBOP ATM VCEP v1.5 BP2 criterion requires documented allelic evidence in an unaffected individual, specifically this variant in trans with a pathogenic/likely pathogenic ATM variant or the relevant cis configuration, with the VCEP points assigned according to phase and setting. The case bundle provides no unaffected adult carrier observation, no second pathogenic/likely pathogenic ATM variant, and no phase information; therefore no BP2 points or strength can be assigned.

Rule

ClinGen HBOP ATM VCEP v1.5 BP2: use the ATM PM3/BP2 points table for unaffected non-A-T individuals carrying the variant with a pathogenic/likely pathogenic variant in trans; -1 point is Supporting, -2 points is Moderate, and 4 or more negative points is Strong.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 directs BP2 assessment to the ATM PM3/BP2 points table; BP2 is Supporting at -1 point, Moderate at -2 points, and Strong at 4 or more negative points.
• For a possible unaffected-carrier BP2 observation, the ATM VCEP specifies an individual aged 18 years or older with no evidence of A-T when the variant is homozygous or in trans with a pathogenic/likely pathogenic ATM variant.
• The consolidated case-evidence bundle contains no qualifying unaffected carrier, second pathogenic/likely pathogenic ATM variant, or phase determination.

Still missing

• No unaffected individual aged at least 18 years carrying this variant was documented.
• No pathogenic/likely pathogenic ATM variant in trans or pathogenic variant in cis was documented.
• No parental, offspring, or other testing established phase.
• No information established absence of ataxia-telangiectasia in an unaffected carrier.

Sources