BCORL1 c.1953C>T, p.(His651=)

Reasoning

c.1953C>T is a synonymous (silent) coding variant (NP_068765.3:p.(His651=)) with no predicted impact on splicing. SpliceAI (via SpliceAI Lookup) reports all four delta scores (acceptor gain/loss, donor gain/loss) at or near zero with a maximum delta score of 0.001, far below the ClinGen-endorsed 0.2 threshold used to flag a possible splice-altering effect, consistent with the case evidence_sentence stating no significant splice impact is predicted. No VCEP/CSPEC exists for BCORL1 to supply an alternative gene-specific BP7 rule or lookup table, so the generic ACMG/AMP BP7 criterion (silent variant, no splicing impact predicted) is applied. Nucleotide-level conservation (e.g., GERP) was not separately assessed in the case bundle; this does not block BP7 under the generic rule, which is satisfied by the splice-prediction arm alone.

Rule

Generic ACMG/AMP BP7: a synonymous (silent) variant for which splicing prediction algorithms predict no impact on the splice consensus sequence.

Evidence considered

• Case compact_evidence.gnomad... normalization shows NM_021946.4:c.1953C>T = NP_068765.3:p.(His651=), confirming a synonymous variant.
• SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' with underlying scores DS_AG=0.0, DS_AL=0.001, DS_DG=0.0, DS_DL=0.0 (max_delta=0.001), all well below the commonly used 0.2 splice-altering threshold.

Still missing

• Nucleotide conservation score (e.g., GERP++) for the c.1953 position was not present in the case evidence bundle.

Sources

Reasoning

PM2 is not met because the variant is not absent from population controls. It is observed three times in gnomAD v4.1 (total AF 2.47622e-06), including three alleles in the European (non-Finnish) subgroup. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0, but the larger gnomAD v4.1 observation overrides an absence-only result and prevents use of PM2 under the generic framework.

Rule

PM2 requires absence or sufficiently rare representation in appropriate population controls; documented observation in gnomAD v4.1 means the absence requirement is not satisfied.

Evidence considered

• gnomAD v4.1 reports the variant in 3/1,211,524 alleles, AF=2.47622e-06, with zero homozygotes.
• The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, but it is present in the more recent and larger gnomAD v4.1 dataset.
• A variant observed in population controls cannot satisfy the generic PM2 absent-from-controls criterion, even when its frequency is very low.

Sources

Reasoning

PP5 is not met because the exact variant NM_021946.4:c.1953C>T is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. Ordinary submissions, aggregate labels, or non-expert assertions would not qualify under the specified rule.

Rule

Apply PP5 only when the exact variant has a ClinVar expert-panel Pathogenic or Likely pathogenic classification; laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar search for the exact variant returned no result; the case bundle records the variant as absent from ClinVar and provides no expert-panel assertion.
• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available to support PP5.

Sources

Reasoning

The variant is not common enough to meet the standalone benign frequency threshold. gnomAD v4.1 reports 3/1,211,524 total alleles (AF 2.47622e-06; 0.00025%), with the highest reported subpopulation AF of 3.35029e-06 in European (non-Finnish) individuals; the maximum group frequency is 8.9e-07. These frequencies are far below a common-variant BA1 threshold.

Rule

BA1 requires a population allele frequency high enough to establish benign status; the observed frequency is far below a common-variant threshold.

Evidence considered

• gnomAD v4.1 reports total AC=3 and AN=1,211,524, AF=2.47622e-06 (0.00025%), total homozygotes=0.
• The highest observed subpopulation frequency is European (non-Finnish) AF=3.35029e-06 (3/895,444 alleles), and grpmax FAF=8.9e-07.
• No applicable BCORL1 VCEP/CSPEC specification was available; generic ACMG/AMP population interpretation was therefore used.

Sources

Reasoning

The observed population frequency does not exceed a disease-specific maximum credible frequency. gnomAD v4.1 reports AF 2.47622e-06 overall and 3.35029e-06 in the highest observed subpopulation, with grpmax FAF 8.9e-07. These values are well below the generic supporting-benign frequency range used for rare Mendelian disease and do not support BS1.

Rule

BS1 requires an allele frequency greater than expected for the disorder; the available frequencies are not high enough to establish excess frequency.

Evidence considered

• gnomAD v4.1 reports 3 alternate alleles among 1,211,524 total alleles, with no homozygotes.
• The highest observed subpopulation AF is 3.35029e-06 in European (non-Finnish) individuals; grpmax FAF is 8.9e-07.
• A BCORL1-specific disease prevalence, penetrance, and maximum credible allele-frequency model was not supplied, but the observed frequency is sufficiently low that it does not approach a BS1 benign-excess-frequency threshold.

Sources

Reasoning

BP6 is not met because the exact variant NM_021946.4:c.1953C>T is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Benign or Likely benign classification. Ordinary submissions, aggregate labels, or non-expert assertions would not qualify under the specified rule.

Rule

Apply BP6 only when the exact variant has a ClinVar expert-panel Benign or Likely benign classification; laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar search for the exact variant returned no result; the case bundle records the variant as absent from ClinVar and provides no expert-panel assertion.
• No exact-variant ClinVar expert-panel Benign or Likely benign classification is available to support BP6.

Sources

Reasoning

No proband-level de novo evidence or parental testing results are provided in the consolidated case-evidence bundle. Therefore, a confirmed de novo occurrence cannot be established.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with confirmed maternity and paternity; no applicable gene-specific specification was available.

Evidence considered

• The case-evidence bundle contains no documented trio analysis, parental testing, or de novo observation for NM_021946.4:c.1953C>T.
• The bundle identifies the variant as a synonymous BCORL1 variant, but variant consequence and population data do not establish de novo status.

Still missing

• Proband genotype and phenotype record linked to this variant
• Validated parental genotypes showing the variant absent in both biological parents
• Information on parental relationships, maternity/paternity, and testing quality

Reasoning

No functional/validated assay evidence is available for NM_021946.4:c.1953C>T (p.(His651=)) in BCORL1. The literature pass returned zero PMIDs for this variant, vcep_materials.json shows no CSPEC/VCEP was found for BCORL1 (case_summary.json cspec.found=false, framework_mode=generic_acmg), and no publications directory content or evidence.json entries describe a functional/splicing/minigene/reporter assay for this specific variant. No BCORL1-specific functional assay framework exists to define validated assay controls or biological relevance thresholds, so this criterion cannot be assessed.

Evidence considered

• literature_pass.json: total_pmids=0, high_priority_papers=[], medium_priority_papers=[], note='No PMIDs found across evidence sources.'
• vcep_materials.json: no cspec url available; final_classification_framework.found=false, source='generic_acmg_fallback', framework_mode=null
• case_summary.json: cspec.found=false, cspec.criteria=[]; framework_mode='generic_acmg'
• fulltext_map.json is empty ({})

Still missing

• No published functional studies (e.g. minigene, RT-PCR, reporter assay) identified that test this exact variant
• No VCEP/CSPEC functional-assay specification exists for BCORL1 to define assay validation standards
• literature_pass.json returned 0 PMIDs; no full-text papers available under the case publications directory to review

Reasoning

No case-control cohort, affected-case count, control count, enrichment statistic, or variant-specific disease association data were provided in the consolidated case-evidence bundle. PS4 cannot be assessed from gene-level context, population frequency, or the absence of ClinVar records.

Rule

Generic ACMG/AMP PS4 requires statistically significant enrichment in affected individuals compared with controls; no applicable BCORL1-specific framework was retrieved.

Evidence considered

• The case-evidence bundle contains no case-control analysis, affected-case count, control count, odds ratio, Fisher exact test, or other enrichment statistic for NM_021946.4:c.1953C>T.
• The bundle reports no literature PMIDs found across evidence sources and provides no variant-specific clinical cohort evidence.

Still missing

• Variant-specific case-control or case-series evidence with affected and control counts and an interpretable enrichment result is unavailable.

Reasoning

No applicable BCORL1 VCEP or gene-specific framework was available, so the generic ACMG/AMP PM3 concept was considered. The case-evidence bundle contains no affected-proband observations, no second pathogenic or likely pathogenic allele, and no phase or inheritance data establishing the tested variant in trans with a disease-causing allele. PM3 therefore cannot be assessed.

Rule

Generic PM3 requires a recessive disease context with the tested variant observed in trans with a pathogenic or likely pathogenic allele in an affected individual; phase and relevant affected-proband evidence are required.

Evidence considered

• The consolidated case-evidence bundle reports no case-level family, phase, affected-proband, or allelic observations for NM_021946.4:c.1953C>T.
• The variant is annotated as synonymous, NM_021946.4:c.1953C>T / NP_068765.3:p.(His651=), but consequence annotation does not establish PM3 without an affected individual and a pathogenic allele in the required phase.
• The bundle states that no BCORL1 CSPEC/VCEP or local gene-specific framework was found; generic ACMG/AMP rules were therefore used.

Still missing

• Affected-proband case observations are not provided.
• No pathogenic or likely pathogenic second allele is documented.
• Phase and inheritance information are unavailable.

Sources

Reasoning

No unconfirmed de novo report, parental origin information, or proband case description is available for this variant. PM6 cannot be applied without evidence suggesting a de novo event when parental testing is incomplete or unavailable.

Rule

Generic ACMG/AMP PM6 may be considered for an assumed de novo occurrence without confirmed maternity and paternity; no qualifying case evidence was provided and no gene-specific specification was available.

Evidence considered

• The consolidated case-evidence bundle reports no literature PMIDs and no case-level parental or de novo observations for NM_021946.4:c.1953C>T.
• Absence or rarity in population databases is not evidence of de novo origin.

Still missing

• A documented affected proband carrying the variant
• Evidence suggesting de novo occurrence
• Parental testing status and reason confirmed maternity/paternity or complete parental genotyping is unavailable

Reasoning

No affected or unaffected relatives, informative meioses, phenotype-matched family members, or variant genotypes across a pedigree are documented. Segregation evidence is therefore unavailable and cannot support PP1.

Rule

Generic ACMG/AMP PP1 requires cosegregation with disease in affected family members; strength escalation depends on the number of informative meioses and the applicable validated framework. No gene-specific specification was available.

Evidence considered

• The consolidated case-evidence bundle contains no pedigree, family segregation analysis, informative meioses, or relative genotype data for this variant.
• The variant's presence in gnomAD and absence from ClinVar do not constitute family segregation evidence.

Still missing

• Pedigree with phenotypic status of relatives
• Genotypes of informative relatives
• Number of informative meioses and co-segregating affected individuals
• Phenotype consistency and assessment of possible phenocopies

Reasoning

The case-evidence bundle does not provide a sufficiently specific patient phenotype or a documented match between the patient's phenotype and a BCORL1-associated disorder. Gene-level disease descriptions and unrelated literature cannot establish PP4 for this variant.

Rule

Generic ACMG/AMP PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology; no applicable BCORL1-specific framework was retrieved.

Evidence considered

• The consolidated case-evidence bundle does not include patient-level phenotype findings, diagnostic features, or a phenotype-to-disease specificity assessment.
• The available BCORL1 literature context is not variant-specific and cannot substitute for documented patient phenotype specificity.

Still missing

• A clinical phenotype description for the patient and a validated, highly specific phenotype-disease match are unavailable.

Reasoning

No BS2 evidence is established. gnomAD v4.1 reports zero homozygotes and contains one or more X-linked allele observations, but the bundle does not provide individual-level phenotype, age, ascertainment, sex-specific clinical status, or penetrance information for the carriers. Population-database presence alone cannot establish that an individual with the variant is a healthy adult unaffected by the relevant BCORL1 disorder.

Rule

BS2 requires observation of the variant in healthy adults in a disease-relevant genotype; aggregate population counts without phenotype and penetrance data are insufficient.

Evidence considered

• gnomAD v4.1 reports total homozygotes=0; the three observed alleles are reported in the European (non-Finnish) group, including one allele among NFE_XY and two among NFE_XX.
• The available record provides population allele counts but no individual clinical phenotype or validated unaffected-adult status.
• Because BCORL1 is X-linked in the available disease context, sex-specific interpretation and penetrance would be needed before using carrier or hemizygote observations for BS2.

Still missing

• No clinically phenotyped healthy adult carrier or hemizygous individual was identified.
• No individual-level gnomAD phenotype, age, ascertainment, or sex-specific clinical information is available.
• BCORL1 disease penetrance and the relevance of absence of homozygotes/hemizygotes in this population dataset are not established for this case.

Sources

Reasoning

No validated functional assay evidence (of any result direction) is available for this variant. As with PS3, the literature pass identified zero PMIDs, there is no BCORL1 CSPEC/VCEP defining a functional assay framework, and no source in the evidence bundle reports an assay result showing normal/wild-type function for this variant. Absent any assay data, benign functional evidence cannot be assessed.

Evidence considered

• literature_pass.json: total_pmids=0, high_priority_papers=[], medium_priority_papers=[], note='No PMIDs found across evidence sources.'
• vcep_materials.json: no cspec url available; final_classification_framework.found=false, source='generic_acmg_fallback'
• case_summary.json: cspec.found=false, cspec.criteria=[]; framework_mode='generic_acmg'
• fulltext_map.json is empty ({})

Still missing

• No published functional studies identified that test this exact variant, in either a pathogenic or benign direction
• No VCEP/CSPEC functional-assay specification exists for BCORL1
• literature_pass.json returned 0 PMIDs; no full-text papers available to review

Reasoning

No tested unaffected relatives, pedigree information, or non-segregation observations are documented. BS4 cannot be assessed because there is no evidence that the variant fails to segregate with disease in an informative family.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected family members or presence in unaffected relatives when the phenotype is expected to be expressed; no qualifying family evidence was provided and no gene-specific specification was available.

Evidence considered

• The consolidated case-evidence bundle provides no family pedigree, unaffected-relative testing, or documented non-segregation for NM_021946.4:c.1953C>T.
• Population frequency and database presence/absence cannot establish non-segregation within a family.

Still missing

• Affected and unaffected relatives with reliable phenotype assessment
• Genotypes for unaffected relatives and other informative family members
• Pedigree structure and number of informative meioses
• Evaluation for reduced penetrance, variable expressivity, and phenocopies

Reasoning

No applicable BCORL1 VCEP or gene-specific framework was available, so the generic ACMG/AMP BP2 concept was considered. The case-evidence bundle contains no affected-proband observations, no documented pathogenic allele, and no phase information showing the tested variant in trans or cis with another clinically classified allele in the inheritance configuration required for BP2. BP2 therefore cannot be assessed.

Rule

Generic BP2 requires an appropriate documented allelic relationship with a pathogenic allele—typically trans for a dominant context or cis for a recessive context—with the relevant inheritance and phase established; absent those observations it is not assessable.

Evidence considered

• The consolidated case-evidence bundle reports no case-level family, phase, affected-proband, or allelic observations for NM_021946.4:c.1953C>T.
• ClinVar has no record for this variant, and no publication or other source in the bundle documents a comparator pathogenic allele or phase relationship that could support BP2.
• The bundle states that no BCORL1 CSPEC/VCEP or local gene-specific framework was found; generic ACMG/AMP rules were therefore used.

Still missing

• No pathogenic or likely pathogenic comparator allele is documented.
• Phase information is unavailable.
• The relevant inheritance configuration and affected-proband context are unavailable.

Sources

Reasoning

No patient-level phenotype, alternative molecular diagnosis, or documented pathogenic variant explaining the phenotype was provided. Therefore BP5 cannot be assessed.

Rule

Generic ACMG/AMP BP5 requires an alternate molecular basis for the patient's phenotype; absence of such information is insufficient to apply the criterion.

Evidence considered

• The consolidated case-evidence bundle contains no documented alternative pathogenic variant or alternative molecular diagnosis that explains the patient's phenotype.
• No patient-level phenotype or diagnostic workup is provided from which an alternative explanation could be established.

Still missing

• The patient's phenotype and any confirmed alternative molecular diagnosis or pathogenic variant are unavailable.