BCOR c.2265C>A, p.(Tyr755Ter)

Reasoning

No official ClinGen VCEP/CSPEC or local gene-specific PVS1 framework is available for BCOR (cspec.found=false, gene_vcep_dir=null), so the generic ACMG/AMP PVS1 decision tree (ClinGen SVI, PMC6185798) is applied per pvs1_variant_assessment. NM_017745.5:c.2265C>A produces NP_060215.4:p.(Tyr755Ter), a nonsense variant in a protein predicted (reference) to be 1722 aa long, so the premature stop occurs well upstream of the normal termination codon. Exon mapping from prefetch/normalization data places c.2265 within the exon spanning c.166-c.2997, whereas the terminal (last) exon begins at c.4875; the PTC therefore falls >50 nucleotides upstream of the last exon-exon junction, which under the ClinGen SVI NMD rule predicts the transcript is a substrate for nonsense-mediated decay (NMD-predicted-to-trigger, not last-exon, not within the terminal 50 bp). No evidence in the case bundle indicates this exon is alternatively spliced, biologically dispensable, or enriched for population-observed LoF variants that would argue for a downgrade, and gnomAD v2.1/v4.1 report the variant as entirely absent (no population LoF-tolerance signal at this residue). BCOR loss of function is an established disease mechanism (pvs1_gene_context: lof_mechanism_supported=true, pvs1_gene_gate='eligible'), consistent with BCOR's known X-linked LOF-disease association (OMIM 300485 was returned in the transcript record). OncoKB's variant-specific annotation independently characterizes the biological effect of this alteration as 'Likely Loss-of-function', corroborating a truncating/NMD-degradation effect. Taken together (nonsense variant, NMD predicted, non-terminal exon, established LOF disease mechanism, no exon-importance or splice-rescue caveats identified), PVS1 is met at full/very-strong strength per the generic ClinGen SVI PVS1 framework.

Rule

ClinGen SVI PVS1 decision tree (generic ACMG fallback, PMC6185798): nonsense variant, NMD predicted (PTC >50nt upstream of last exon-exon junction, not in terminal exon), established gene-level LOF disease mechanism, no exon-importance/splice-rescue caveats identified -> PVS1 at full/very-strong strength.

Evidence considered

• pvs1_variant_assessment.json classifies NM_017745.5:c.2265C>A as consequence_class='nonsense', variant_bucket='nonsense', and recommends the generic PVS1 framework (PMC6185798) with suggested_default_strength='PVS1', subject to confirming NMD prediction and exon importance.
• prefetch.json exon/CDS coordinate map (selector_short) shows the exon containing c.2265 spans c.166-c.2997, while the terminal exon spans c.4875-*863 (3'UTR); the resulting PTC at c.2265 (p.Tyr755Ter) is far more than 50 nt from the final exon-exon junction, satisfying the ClinGen SVI criterion for NMD-predicted transcripts.
• prefetch.json predicted reference protein length is 1722 amino acids (position_last_original=1722), confirming the p.Tyr755Ter truncation removes the majority of the protein, consistent with a damaging LOF outcome if NMD were to be escaped.
• pvs1_gene_context.json states lof_mechanism_supported=true and pvs1_gene_gate='eligible', concluding generic PVS1 framework assessment is permitted for BCOR, while flagging in 'cautions' that no official CSPEC/VCEP framework exists and the generic fallback should follow PMC6185798.
• oncokb evidence_sentence and biological_effect field characterize this specific variant (BCOR Y755*) as 'Likely Loss-of-function', corroborating the LOF interpretation independent of the ACMG PVS1 mechanistic reasoning.
• gnomAD v2.1 and v4.1 both report the variant as entirely absent, providing no population evidence of LoF tolerance at this position that would argue against applying PVS1 at full strength.
• case_summary.json spliceai evidence_sentence shows max delta score = 0.00, indicating no competing splice-altering signal that would change the NMD/consequence interpretation for this substitution.

Still missing

• The gene-level PVS1 eligibility gate rests entirely on a literature-only germline search; the retrieved 'supporting' papers (PMID:42409735, PMID:38019014, PMID:33178592, PMID:37406166, PMID:40799249) primarily concern germline RUNX1/GATA2/VHL predisposition syndromes in which BCOR mutations appear only as incidental somatic/acquired events, not dedicated reports of primary germline BCOR loss-of-function disease (e.g., oculofaciocardiodental syndrome); a human reviewer should confirm the germline LOF mechanism against the recognized BCOR-OFCD/MCOPS2 literature rather than this automated search output.
• No exon-level constraint, expression (pext), or alternative-splicing annotation was available in the bundle to confirm the exon containing c.2265 is not a minor/dispensable isoform-specific exon.
• No official CSPEC/VCEP PVS1 specification exists for BCOR in this pipeline; assessment relies on the generic ClinGen SVI framework fallback only.

Sources

Reasoning

PM2 is met at supporting strength. NM_017745.5:c.2265C>A in BCOR is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. The available population evidence therefore supports an absent/extremely rare population frequency, with no reported homozygote or hemizygote count. Because BCOR is on the X chromosome and the bundle supplies no sex-stratified allele denominators or disease-specific maximum credible allele frequency, the evidence is retained at supporting strength rather than upgraded.

Rule

Generic ACMG/AMP 2015 fallback (generic_acmg_combination_rules; Richards et al. 2015, PMID:25741868): PM2 supports a variant that is absent from population databases or present at an extremely low frequency. Applied at supporting strength because no gene-specific specification or disease-specific maximum credible allele frequency is available.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.
• The variant is an X-linked BCOR nonsense variant; the bundle does not provide sex-stratified population denominators or disease-specific frequency modeling.

Still missing

• Sex-stratified X-chromosome allele counts and coverage details are not available in the bundle.
• No disease-specific maximum credible allele frequency incorporating prevalence, penetrance, and genetic heterogeneity is available.

Sources

Reasoning

SpliceAI predicts no splice impact for this variant, with a max delta score of 0.00 across all four categories (acceptor gain/loss, donor gain/loss), well below the widely used clinical threshold of ≥0.2 for a possible splice-altering effect established by SpliceAI's original validation (Jaganathan et al. 2019, Cell, PMID 30661751 - a publication known to this reviewer and not part of the case source registry). This is a computational prediction of no splicing disruption, independently supporting a benign impact on splicing for this exonic substitution. No governing BCOR VCEP/CSPEC lookup table exists to override this generic determination. Because the variant's dominant molecular mechanism is nonsense-mediated truncation (evaluated separately under PVS1), this BP4 code reflects only the splice-impact sub-path owned by this group and does not stack with or substitute for PVS1.

Rule

generic_acmg_bp4

Evidence considered

• SpliceAI Lookup result: max_delta_score=0.00 (all four DS_AG/AL/DG/DL = 0.0) for NM_017745.5:c.2265C>A, retrieved from evidence.json/case_summary.json.
• Widely accepted SpliceAI threshold of delta score >=0.2 to flag a possible splice-altering effect, from Jaganathan KM et al., 'Predicting Splicing from Primary Sequence with Deep Learning', Cell 2019, PMID 30661751; the observed 0.00 score is far below this threshold, supporting no predicted splice disruption.

Sources

Reasoning

No governing VCEP/CSPEC was found for BCOR (framework_mode: generic_acmg, cspec.found=false), so generic ACMG/AMP computational-evidence handling applies. The variant NM_017745.5:c.2265C>A / NP_060215.4:p.(Tyr755Ter) is a nonsense (stop-gain) substitution, not a missense or synonymous change, and does not lie in a canonical splice consensus sequence (canonical_splice_consensus=false), so the missense in-silico pathway (REVEL/BayesDel/aGVGD) is not the applicable predictor class for this substitution type. Evaluating the splice-impact path instead: SpliceAI reports a max delta score of 0.00 across all four splice-altering categories (DS_AG/AL/DG/DL all 0.00), far below any threshold used to support a splice-disruption prediction, so there is no computational evidence supporting a deleterious splicing effect. Separately, a BayesDel score (0.66) was retrieved from local BayesDel_170824_noAF data, but per this pipeline's evidence-calibration policy no verified published threshold/PMID is available for BayesDel, so it must be treated as not_available for PP3/BP4 regardless of the raw value. REVEL was not available (no REVEL ZIP found for this genomic position). With no valid deleteriousness-supporting predictor score, PP3 is not met.

Rule

generic_acmg_pp3

Evidence considered

• SpliceAI Lookup result: DS_AG=0.0, DS_AL=0.0, DS_DG=0.0, DS_DL=0.0, max_delta_score=0.00 for NM_017745.5:c.2265C>A (evidence.json/case_summary.json spliceai block).
• Variant is classified as consequence_class=nonsense with canonical_splice_consensus=false (pvs1_variant_assessment), meaning the missense-predictor PP3 pathway is not applicable to this stop-gain substitution.
• BayesDel score 0.66 was retrieved (source_registry key 'bayesdel') but per this pipeline's evidence policy no verified published threshold/PMID exists for BayesDel yet, so it is treated as not_available for PP3/BP4 rather than being used to support pathogenicity.
• REVEL was queried but not found for this variant's genomic position (prefetch.json/evidence.json revel block: 'No REVEL ZIP found for chrX:40073081').

Still missing

• REVEL score unavailable for this position (no REVEL ZIP found for chrX:40073081), so missense conservation-based in-silico evidence could not be evaluated even if the variant type were reconsidered.
• BayesDel score exists (0.66) but has no verified published calibration threshold accepted by this pipeline, so it cannot be used to support or refute PP3/BP4.
• No BCOR-specific VCEP/CSPEC PP3/BP4 lookup table was available to pre-assign a code.

Sources

Reasoning

BA1 is not met. NM_017745.5:c.2265C>A (BCOR; p.Tyr755Ter) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. No population allele frequency approaches a stand-alone benign threshold, and no threshold artifact or common ancestry-specific observation is reported.

Rule

Generic ACMG/AMP 2015 fallback: BA1 requires a population allele frequency supporting a stand-alone benign classification; no such frequency is present.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Sources

Reasoning

BS1 is not met. The variant is absent from the available population datasets, so there is no allele frequency above the expected disease-prevalence threshold or a gene-specific benign-frequency threshold. Disease prevalence, penetrance, and an explicit BCOR frequency threshold are not provided, but the observed data do not support BS1.

Rule

Generic ACMG/AMP 2015 fallback: BS1 requires an allele frequency greater than expected for the disorder; no such observation is available.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Sources

Reasoning

No proband-level de novo evidence is provided in the consolidated case-evidence bundle. The bundle contains no documented parental testing, maternity/paternity confirmation, parental genotype results, or phenotype-specific de novo case report for NM_017745.5:c.2265C>A (BCOR p.Tyr755Ter). Therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with confirmed maternity and paternity; absent those data, PS2 is not assessed.

Evidence considered

• The consolidated case-evidence bundle was reviewed for proband, parental testing, de novo, and family-level evidence; no qualifying PS2 evidence was present.
• The available literature entries were functional/somatic BCOR publications and did not document this germline variant in a de novo proband context.

Still missing

• Documented affected proband phenotype and clinical diagnosis
• Parental testing results for the variant
• Confirmation of maternity and paternity
• Assessment of relevant parental mosaicism or sample quality

Reasoning

No gene-specific VCEP/CSPEC exists for BCOR (cspec.found = false; final_classification_framework.source = generic_acmg_fallback), so generic ACMG/AMP PS3 requirements apply: a validated functional assay (with appropriate positive/negative controls) that specifically tests the effect of this exact variant (NM_017745.5:c.2265C>A / p.Tyr755Ter) on protein function. The literature packet contains 5 BCOR papers (PMID:22012066, PMID:22237022, PMID:24047651, PMID:25550361, PMID:26847029), all discovery/cohort sequencing studies characterizing recurrent somatic BCOR loss-of-function mutations in AML/MDS/retinoblastoma or Bcor conditional-knockout mouse models of general BCOR loss of function -- none report a validated functional assay of this specific variant (Y755*). OncoKB's 'Likely Loss-of-function' biological-effect label is a curated aggregate classification, not primary functional assay data, and per instructions a criterion cannot be inferred from another source's classification/label. No variant-specific functional assay evidence was found; PS3 cannot be applied.

Evidence considered

• case_summary.json cspec.found = false and vcep_materials.json note = 'no cspec url available', confirming no BCOR VCEP/CSPEC PS3 assay specification exists for this case.
• literature_packet in case_summary.json lists 5 high-priority BCOR papers all tagged theme='functional' but candidate_criteria=[] (empty), and all are gene-level discovery/mechanistic studies, not variant-specific functional assays of Y755*.
• OncoKB evidence_sentence in evidence.json states biological_effect 'Likely Loss-of-function' and classification 'Likely Oncogenic' -- this is a curated somatic-oncogenicity classification/label, not raw functional assay data, and per grouping instructions must not be used to infer PS3 status.

Still missing

• No validated functional assay (e.g., reporter, complementation, biochemical activity assay) specifically testing NM_017745.5:c.2265C>A / p.Tyr755Ter was identified in the retrieved literature.
• No CSPEC/VCEP-approved assay list or PS3 strength calibration table is available for BCOR.

Reasoning

PS4 requires case-control evidence showing that the disease is significantly more prevalent in affected individuals than in controls. The case-evidence bundle contains no variant-specific affected-case count, control comparison, enrichment estimate, statistical test, or disease-focused cohort evidence for NM_017745.5:c.2265C>A (BCOR; p.Tyr755Ter). The available literature packet concerns somatic BCOR studies and does not document this exact germline variant or provide PS4 case-control data. PS4 cannot be applied from gene-level disease association, OncoKB context, or another source's classification.

Rule

generic ACMG/AMP PS4: disease prevalence is significantly increased in affected individuals compared with controls; requires variant-specific case-control evidence

Evidence considered

• The consolidated case-evidence bundle provides no PS4 case-control counts, odds ratio, confidence interval, p-value, or variant-specific disease-enrichment result.
• The retrieved literature packet contains only somatic BCOR publications and none is documented as reporting the exact variant NM_017745.5:c.2265C>A.

Still missing

• Variant-specific affected-case and control counts or a validated case-control enrichment estimate are unavailable.
• No disease-specific cohort or statistical significance supporting enrichment was identified.

Sources

Reasoning

PM3 cannot be assessed because the case bundle contains no affected-proband observations, no second pathogenic or likely pathogenic variant, and no validated phase or inheritance information showing this variant in trans with a pathogenic variant. BCOR-specific VCEP/CSPEC guidance was not available, so the generic ACMG/AMP framework was used.

Rule

Generic ACMG/AMP PM3: apply only when the variant is observed in trans with a pathogenic or likely pathogenic variant in an affected individual with a recessive disorder, with strength determined by the number and quality of informative observations. Do not apply without documented phase and relevant affected-proband evidence.

Evidence considered

• The case bundle identifies BCOR and reports no applicable gene-specific VCEP/CSPEC framework.
• The case bundle provides no family, segregation, affected-proband, allelic, phase, or inheritance evidence for PM3.
• The generic ACMG/AMP framework requires evidence of a variant in trans with a pathogenic variant for recessive disease contexts; that evidence is absent here.

Still missing

• Affected-proband or affected-case observations involving this variant are not provided.
• No second pathogenic or likely pathogenic variant is documented.
• Phase information (in trans or cis) is not provided.
• Inheritance mode and parental testing are not provided.

Reasoning

No assumed de novo observation is documented for NM_017745.5:c.2265C>A. The consolidated case-evidence bundle contains no affected proband case description, parental genotype information, or report establishing that the variant arose de novo without confirmed maternity and paternity. Therefore PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6 applies to an assumed de novo occurrence in an affected individual when maternity and paternity are not confirmed; no such observation is documented here.

Evidence considered

• The consolidated case-evidence bundle was reviewed for assumed de novo, proband, parental, and phenotype evidence; no qualifying PM6 evidence was present.
• The available literature entries did not report this variant in a germline de novo clinical case.

Still missing

• A documented affected proband carrying the variant
• Parental genotype information or an explicit assumed-de-novo basis
• Phenotype consistency with the relevant BCOR-associated disorder
• Evidence excluding an inherited or technically unresolved variant

Reasoning

No segregation analysis is provided for NM_017745.5:c.2265C>A. The consolidated case-evidence bundle contains no family pedigree, affected or unaffected relatives, genotype-phenotype concordance, or number of informative meioses. PP1 therefore cannot be assessed or strengthened.

Rule

Generic ACMG/AMP PP1 requires co-segregation with disease in multiple affected family members; no family segregation data are available.

Evidence considered

• The consolidated case-evidence bundle was reviewed for pedigree, relatives, meioses, segregation, and genotype-phenotype data; no qualifying PP1 evidence was present.
• The listed publications were not relevant clinical segregation studies for this variant.

Still missing

• Pedigree identifying affected and unaffected relatives
• Variant testing results for informative relatives
• Phenotype classification for each tested relative
• Number of informative meioses and segregation observations

Reasoning

PP4 requires a patient's phenotype or highly specific phenotype and/or family history to be highly specific for a disease with a single-gene etiology. No patient phenotype, clinical presentation, family history, or disease-specific diagnostic context is provided in the case-evidence bundle for this variant. Therefore PP4 cannot be assessed and cannot be inferred from BCOR gene function, a truncating consequence, OncoKB, or a general disease association.

Rule

generic ACMG/AMP PP4: patient's phenotype or family history is highly specific for a disease with a single-gene etiology

Evidence considered

• The consolidated case-evidence bundle contains no patient-level phenotype, family history, or disease-specific clinical description for this case.
• Gene-level BCOR loss-of-function context is not sufficient to establish PP4 without a highly specific patient phenotype.

Still missing

• Patient phenotype and diagnostic features are unavailable.
• No phenotype specificity analysis or single-gene disease match is documented.

Sources

Reasoning

BS2 cannot be assessed from the case bundle. No documented observation of this variant in healthy adult individuals, unaffected relatives, or individuals with a phenotype inconsistent with BCOR-related disease is provided. Absence from population databases and absence of homozygote observations do not by themselves establish BS2, particularly for an X-linked gene without sex-specific carrier and hemizygote data.

Rule

Generic ACMG/AMP 2015 fallback: BS2 requires observation in healthy adults or other appropriately unaffected individuals; population absence is not sufficient.

Still missing

• Documented observation of the exact variant in appropriately phenotyped healthy adults or unaffected individuals, with relevant sex, zygosity/hemizygosity, age, and penetrance context.

Reasoning

No gene-specific VCEP/CSPEC exists for BCOR, so generic ACMG/AMP BS3 requirements apply: a validated functional assay specifically showing no damaging effect for this exact variant. None of the 5 retrieved BCOR papers report any functional assay result for this variant (or any assay result at all showing normal/wild-type function) -- they are cohort mutation-discovery and general Bcor-knockout mechanistic studies. No evidence of a benign functional assay result was found; BS3 cannot be applied. Independently, this variant is a nonsense change (p.Tyr755Ter) predicted to truncate the protein, which biologically argues against a benign functional readout, but no assay data (positive or negative) was located to formally assess BS3.

Evidence considered

• case_summary.json cspec.found = false and vcep_materials.json note = 'no cspec url available', confirming no BCOR VCEP/CSPEC BS3 assay specification exists for this case.
• None of the 5 retrieved BCOR papers (PMID:22012066, PMID:22237022, PMID:24047651, PMID:25550361, PMID:26847029) report assay results specific to this variant; all are cohort discovery or general Bcor loss-of-function mechanistic studies.

Still missing

• No functional assay data (of any direction) for NM_017745.5:c.2265C>A / p.Tyr755Ter was found in the retrieved literature.
• No CSPEC/VCEP-approved assay list or BS3 strength calibration table is available for BCOR.

Reasoning

No non-segregation evidence is provided for NM_017745.5:c.2265C>A. The consolidated case-evidence bundle contains no tested unaffected relatives, no reliable genotype results in unaffected family members, and no phenotype assessment establishing failure to segregate with disease. BS4 therefore cannot be assessed.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected family members or reliable non-segregation evidence; no such family data are available.

Evidence considered

• The consolidated case-evidence bundle was reviewed for unaffected relatives and non-segregation findings; no qualifying BS4 evidence was present.
• The available literature entries did not provide a clinical family study demonstrating non-segregation of this variant.

Still missing

• Tested unaffected relatives with reliable variant results
• Well-defined disease status and age-related penetrance context for relatives
• Pedigree and number of informative non-segregating observations
• Assessment of phenocopies, reduced penetrance, and technical limitations

Reasoning

BP2 cannot be assessed because the case bundle contains no documented second variant, no phase information, and no inheritance or disease-model information establishing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder.

Rule

Generic ACMG/AMP BP2: apply only when the variant is observed in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder, with appropriate disease-model and phase evidence. Do not apply without documentation of the second variant and phase.

Evidence considered

• The case bundle provides no allelic, phase, family, or inheritance evidence for BP2.
• The generic ACMG/AMP framework requires documented phase and an appropriate disease model before BP2 can be applied; neither is available in this case.

Still missing

• No second variant in the same individual is documented.
• Phase information (in trans or cis) is not provided.
• Inheritance mode and the applicable disease model are not provided.
• No affected-proband or family-level allelic observations are provided.

Reasoning

BP5 requires a pathogenic variant in the same gene or another gene that explains the patient's phenotype, supporting a benign interpretation of the evaluated variant. The case-evidence bundle contains no patient-level phenotype, no competing pathogenic variant, and no molecular diagnosis that explains the case independently of NM_017745.5:c.2265C>A. Therefore BP5 cannot be assessed.

Rule

generic ACMG/AMP BP5: variant observed in a patient with an alternate pathogenic variant that explains the phenotype

Evidence considered

• The consolidated case-evidence bundle does not report an alternate pathogenic variant or an alternate molecular diagnosis for this case.
• Without patient phenotype and an independently explanatory pathogenic variant, BP5 cannot be applied.

Still missing

• Patient phenotype and molecular diagnostic context are unavailable.
• No independently pathogenic alternate variant explaining the phenotype is documented.

Sources