PHF6 c.859G>C, p.(Gly287Arg)

Reasoning

NM_001015877.1:c.859G>C (p.Gly287Arg) is reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the generic ACMG/AMP framework, absence from reference population databases supports PM2 at supporting strength for a rare disorder. Confidence is moderated because allele-number, coverage, and ancestry-specific metrics are unavailable for gnomAD v2.1/v4.1, while the gnomAD-Canada record has AN=0.

Rule

Generic ACMG/AMP PM2: the variant is absent from controls in population databases; applied at supporting strength because no PHF6-specific specification was retrieved.

Evidence considered

• The consolidated evidence reports NM_001015877.1:c.859G>C as absent from gnomAD v2.1.
• The consolidated evidence reports NM_001015877.1:c.859G>C as absent from gnomAD v4.1.
• The consolidated evidence reports the variant as absent from gnomAD-Canada v1.0, with AC=0 and AF=0.0; the accompanying AN=0 is a data-quality limitation.
• No ancestry-specific frequency, homozygote count with a valid denominator, or population-frequency threshold artifact establishes a conflicting common allele.

Still missing

• Confirm the exact variant's absence using quantitative gnomAD allele counts, allele numbers, callable coverage, and ancestry-specific maximum frequency.
• Confirm that the database-negative result is not caused by transcript/build mismatch or insufficient coverage at the PHF6 locus.
• No PHF6-specific population-frequency or maximum credible allele-frequency specification was available.

Sources

Reasoning

No governing CSPEC/VCEP framework is available for PHF6 (cspec.found=false); generic ACMG/AMP applies. SpliceAI predicts negligible splice impact for NM_001015877.1:c.859G>C (max delta score 0.002; DS_AG 0.0, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0), well below the widely used 0.2 delta-score threshold from the original SpliceAI validation study (Jaganathan et al. 2019, PMID 30661751) for a splice-altering prediction. This calibrated computational evidence supports no splicing-disruptive effect, warranting BP4 at supporting strength via the splice-impact path. The missense in-silico path (REVEL, BayesDel) could not additionally contribute: REVEL was not found for this position, and the retrieved BayesDel score (0.545598) is not usable because no verified published calibration threshold/table can currently be cited for BayesDel by this pipeline, so it is excluded rather than interpreted numerically. BP4 is therefore applied on the single calibrated splice-impact line of evidence at supporting strength.

Rule

generic_acmg_bp4_spliceai

Evidence considered

• SpliceAI Lookup (spliceai source) reports max delta score 0.002 (DS_AG 0.0, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0) for NM_001015877.1:c.859G>C, far below the ~0.2 delta-score threshold established as a splice-altering cutoff in the original SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), supporting no predicted splicing impact.
• BayesDel score of 0.545598 was retrieved from the local predictor but is excluded from BP4 scoring because no verified published threshold/table is currently citable for BayesDel by this pipeline.
• REVEL prefetch failed ('No REVEL ZIP found for chrX:134417193'), so no missense REVEL-based evidence contributes to BP4.

Still missing

• Missense computational evidence (REVEL, BayesDel) is not usable to independently corroborate BP4 for the missense change itself: REVEL absent, BayesDel uncalibrated per pipeline policy
• No governing gene-specific VCEP PP3/BP4 lookup spreadsheet available for PHF6

Sources

Reasoning

No governing CSPEC/VCEP framework is available for PHF6 (cspec.found=false; vcep_materials empty); generic ACMG/AMP applies. This is a missense variant (NP_001015877.1:p.(Gly287Arg)). The missense in-silico path lacks usable calibrated evidence: REVEL was not found for this position (prefetch error: 'No REVEL ZIP found for chrX:134417193'), and although a local BayesDel score (0.545598) was retrieved, this pipeline has no verified published threshold/table it can cite for BayesDel, so per policy the score must be treated as not_available for PP3/BP4 rather than interpreted numerically. No aGVGD or other calibrated missense predictor data is present. On the splice-impact path, SpliceAI shows negligible predicted disruption (max delta score 0.002; DS_AG 0.0, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0), which does not support a splicing-based pathogenic mechanism. With no calibrated missense predictor evidence supporting damage and no splice-disruption signal, PP3 is not met.

Rule

generic_acmg_pp3

Evidence considered

• SpliceAI Lookup (spliceai source) reports max delta score 0.002 (DS_AG 0.0, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0) for NM_001015877.1:c.859G>C, far below any splice-disrupting threshold, indicating no predicted splicing impact.
• Local BayesDel lookup returned a score of 0.545598 for this variant, but per pipeline policy no verified published BayesDel threshold/table can currently be named and cited, so this score is treated as not_available for PP3/BP4 rather than interpreted as pathogenic or benign.
• REVEL prefetch failed with 'No REVEL ZIP found for chrX:134417193', so no REVEL score is available for this variant.

Still missing

• REVEL score unavailable for this variant/position (no REVEL ZIP coverage for chrX:134417193)
• BayesDel score exists (0.545598) but no verified published calibration threshold/table is available to this pipeline, so it cannot be used numerically for PP3/BP4
• No aGVGD or other calibrated missense in-silico predictor data present
• No governing gene-specific VCEP PP3/BP4 lookup spreadsheet available for PHF6 to pre-assign this code

Sources

Reasoning

PP5 is not met because the exact variant NM_001015877.1:c.859G>C is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. Ordinary submissions, aggregate labels, and non-expert assertions would not qualify, even if present.

Rule

Apply PP5 only when an exact-variant ClinVar expert-panel classification is Pathogenic or Likely pathogenic; do not use ordinary laboratory submissions, aggregate labels, or non-expert assertions.

Evidence considered

• ClinVar exact-variant review found no result for NM_001015877.1:c.859G>C; therefore no expert-panel Pathogenic/Likely pathogenic assertion is available to support PP5.

Sources

Reasoning

The variant is reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no population frequency at or above the BA1 threshold is demonstrated. Quantitative allele-number and coverage metrics are unavailable for gnomAD v2.1 and v4.1, so the absence should be verified before treating this as a definitive exclusion of common variation.

Rule

Generic ACMG/AMP BA1: an allele frequency sufficiently high to establish benign status; no applicable PHF6-specific VCEP rule was available.

Evidence considered

• The consolidated evidence reports NM_001015877.1:c.859G>C as absent from gnomAD v2.1.
• The consolidated evidence reports NM_001015877.1:c.859G>C as absent from gnomAD v4.1.
• The consolidated evidence reports the variant as absent from gnomAD-Canada v1.0, with AC=0, AN=0, AF=0.0, and homozygote count 0; AN=0 is not an interpretable population denominator.
• No reliable population frequency, ancestry-specific frequency, or coverage metric reaches a BA1 threshold.

Still missing

• Allele count, allele number, ancestry-specific maximum frequency, and callable coverage are not available for gnomAD v2.1 or v4.1.
• The gnomAD-Canada record reports AN=0, which may represent a data-return artifact rather than a meaningful denominator.

Sources

Reasoning

No elevated population frequency is demonstrated. The variant is reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so the available evidence does not support a frequency above the disease-specific benign threshold. The absence of quantitative denominators and coverage data limits confidence in the database-negative result.

Rule

Generic ACMG/AMP BS1: allele frequency is greater than expected for the disorder; no applicable PHF6-specific VCEP rule was available.

Evidence considered

• The variant is reported absent from gnomAD v2.1 and gnomAD v4.1.
• The variant is reported absent from gnomAD-Canada v1.0; the reported AN=0 is a threshold/data-quality caveat rather than evidence of a well-powered negative observation.
• Because no nonzero allele frequency is reported, the available population data do not meet a BS1 elevated-frequency threshold.

Still missing

• No allele-number, coverage, or ancestry-specific frequency data are available for the principal gnomAD datasets.
• A disease prevalence, penetrance, and maximum credible population-frequency calculation specific to PHF6/Börjeson-Forssman-Lehmann syndrome is not included in the case bundle.

Sources

Reasoning

BP6 is not met because the exact variant NM_001015877.1:c.859G>C is reported as absent from ClinVar, with no exact-variant ClinVar expert-panel Benign or Likely benign classification. Ordinary submissions, aggregate labels, and non-expert assertions would not qualify, even if present.

Rule

Apply BP6 only when an exact-variant ClinVar expert-panel classification is Benign or Likely benign; do not use ordinary laboratory submissions, aggregate labels, or non-expert assertions.

Evidence considered

• ClinVar exact-variant review found no result for NM_001015877.1:c.859G>C; therefore no expert-panel Benign/Likely benign assertion is available to support BP6.

Sources

Reasoning

PS1 requires a different nucleotide change producing the identical amino acid change (p.Gly287Arg via a different codon) that has already been established as pathogenic. This variant is absent from ClinVar (no result found for PHF6 c.859G>C), and no other same-amino-acid-change comparator variant data is present anywhere in the case bundle (no VCEP/CSPEC framework, no literature hits, no clinvar_submission_audit content surfaced). There is no evidence source in the bundle to confirm or refute a prior pathogenic classification of any variant producing p.Gly287Arg.

Evidence considered

• case_summary.json clinvar block: 'This variant is absent from ClinVar' (variation_ids empty, no submissions)
• evidence.json clinvar entry: search_status 'no_result', found false

Still missing

• No ClinVar record for this variant or any other codon-859 substitution producing the same p.(Gly287Arg) change was found in the case bundle
• No PHF6 CSPEC/VCEP framework available to define gene-specific PS1 rules
• No literature search results identify a same-amino-acid-change comparator variant

Sources

Reasoning

No proband-level de novo observation is documented in the case-evidence bundle. There is no documented parental testing demonstrating that NM_001015877.1:c.859G>C (p.Gly287Arg) is absent in both biological parents, and no validated maternity/paternity information is provided.

Rule

Generic ACMG/AMP 2015 PS2: de novo occurrence in a patient with the disease and no family history, with maternity/paternity confirmed as applicable; do not apply without documented parental testing and relevant phenotype.

Evidence considered

• The case-evidence bundle reports no case literature, no ClinVar record, and no family or parental testing data for this variant.
• PS2 requires documented de novo occurrence in the proband with appropriate parental testing; that evidence is not available for this case.
• Generic ACMG/AMP fallback is applicable because no PHF6-specific VCEP/CSPEC framework was retrieved.

Still missing

• Proband phenotype and clinical indication
• Testing results for both biological parents
• Confirmation of biological parentage
• Laboratory method, coverage, and mosaicism assessment

Sources

Reasoning

No ClinGen VCEP or gene-specific framework is available for PHF6 (cspec.found=false; final_classification_framework.found=false, generic_acmg_fallback). No PMIDs were identified for this variant by the literature pass (literature_pass.json: total_pmids=0, note='No PMIDs found across evidence sources'), and no functional/enzymatic assay data (e.g. transactivation, chromatin binding, degradation, splicing minigene) for NP_001015877.1:p.(Gly287Arg) was located in evidence.json, prefetch.json, or vcep_materials.json. OncoKB was queried but explicitly returned no variant-specific reviewed functional evidence ('did not identify variant-specific reviewed functional evidence for this variant'), only gene-level narrative context, which cannot support PS3.

Evidence considered

• OncoKB (queried at https://www.oncokb.org/gene/PHF6/G287R) returned 'Unknown Oncogenic Effect' classification and explicitly flagged the result as not variant-specific reviewed evidence, only gene-level curated context about PHF6 as a chromatin-binding protein altered in hematologic malignancies.
• literature_pass.json reports total_pmids=0 with note 'No PMIDs found across evidence sources', meaning no candidate functional-study publications for this variant were surfaced for review.
• No cspec/VCEP-specific PS3 assay-validation table was found (cspec.found=false in both case_summary.json and prefetch.json).

Still missing

• No validated functional/biochemical assay (e.g. chromatin-binding, transcriptional repression, PHD-finger structural, or cell-based rescue assay) for this specific missense variant was found in any prefetched source.
• No published literature identified mentioning c.859G>C / p.(Gly287Arg) specifically; a targeted PubMed/Sci-Hub search for functional characterization of this exact variant was not performed within this evidence bundle and should be done before finalizing PS3 as not_met vs not_assessed.

Reasoning

No case-control cohort, affected-case count, control count, enrichment estimate, or statistical analysis for NM_001015877.1:c.859G>C was provided. PS4 cannot be assessed from gene-level disease context or absence of population data.

Rule

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

Evidence considered

• The consolidated case-evidence bundle reports no literature PMIDs and contains no variant-specific case-control data for NM_001015877.1:c.859G>C (NP_001015877.1:p.Gly287Arg).

Still missing

• Variant-specific affected-case and control counts are unavailable.
• No case-control enrichment statistic or validated phenotype prevalence analysis is available.

Reasoning

PM1 requires the variant to fall in a well-established mutational hotspot or critical functional domain without benign variation. No PHF6 CSPEC/VCEP framework is available (cspec.found: false, gene_vcep_dir: null), and the cancerhotspots.org query for PHF6 G287 returned no result. No structural/domain annotation for residue 287 (e.g., PHD/ePHD zinc-finger domain boundaries) is present anywhere in the case bundle, and no publications were retrieved that describe the domain architecture around residue 287. Without a bundled source characterizing this residue as domain-critical or hotspot, PM1 cannot be safely applied.

Evidence considered

• hotspots.json/evidence.json: cancerhotspots.org query 'PHF6 G287' returned no_result, 'This variant does not lie in a statistically significant hotspot' (somatic hotspot context only, not germline domain data)
• oncokb evidence_sentence: no variant-specific reviewed functional evidence identified; only gene-level context that PHF6 is frequently altered in hematologic malignancies, insufficient to establish residue-level domain criticality

Still missing

• No cancer hotspot data available for PHF6 G287 (hotspots.found: false, 'does not lie in a statistically significant hotspot' per available screen, but this reflects cancer somatic hotspot data only, not germline domain criticality)
• No CSPEC/VCEP PM1 domain framework for PHF6 present in this case
• No structural/domain boundary data for residue 287 present in the bundle to confirm placement within a critical functional domain
• No literature full text retrieved characterizing residue 287 domain context

Sources

Reasoning

No affected-proband observations, second pathogenic/likely pathogenic allele, phase information, or inheritance data are available in the case-evidence bundle. Therefore the generic PM3 requirement for evidence that the variant is observed in trans with a pathogenic variant in an affected individual cannot be assessed.

Rule

Generic ACMG/AMP PM3: consider evidence when the variant is observed in trans with a pathogenic variant in an affected individual with a recessive disorder; phase and disease context must be established.

Evidence considered

• The governing framework record reports no PHF6-specific VCEP/CSPEC specification, so generic ACMG/AMP fallback was used.
• The consolidated case-evidence bundle contains no family, affected-proband, allelic, phase, or inheritance observations relevant to PM3.

Still missing

• Affected-proband case data are absent.
• A pathogenic or likely pathogenic second allele is not documented.
• Phase (trans/cis) is not documented.
• Inheritance mode and segregation information are not documented.

Sources

Reasoning

PM5 requires a previously established pathogenic missense variant at the same residue with a different amino acid substitution. The bundled pm5_candidates_summary explicitly reports pm5_mode 'unknown' and eligible_for_classic_pm5_search: false, with zero candidates seen (total_candidates_seen: 0), and instructs that classic same-residue PM5 semantics could not be confirmed and automatic candidate harvesting was skipped. No other source in the bundle supplies alternate-residue pathogenic comparator variants at codon 287.

Evidence considered

• pm5_candidates_summary: recommendation.level 'not_applicable', summary 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting', hermes_instruction to not apply PM5 from this artifact alone
• clinvar evidence_sentence: variant absent from ClinVar, no submissions surfaced

Still missing

• pm5_candidates.json harvesting was explicitly skipped for this case (pm5_mode: unknown, eligible_for_classic_pm5_search: false, total_candidates_seen: 0)
• No ClinVar data available (variant and gene searches returned no usable comparator records)
• No literature identifies other pathogenic missense substitutions at residue 287

Sources

Reasoning

No presumed de novo observation is documented. The bundle contains no report of the variant in a proband with apparently unaffected parents, and no parental testing or phenotype information is available to support a presumed de novo finding.

Rule

Generic ACMG/AMP 2015 PM6: presumed de novo occurrence in a patient with the disease and no family history, without confirmation of maternity/paternity; apply only when case-level evidence supports the presumption.

Evidence considered

• The case-evidence bundle contains no proband/family description and no parental genotyping results.
• PM6 is not applicable from variant absence in population or disease databases; a case-specific presumed de novo observation is required.
• Generic ACMG/AMP fallback is applicable because no PHF6-specific VCEP/CSPEC framework was retrieved.

Still missing

• Proband phenotype and clinical indication
• Parental clinical status
• Parental testing or an explicit basis for presuming de novo occurrence
• Confirmation of biological parentage

Sources

Reasoning

No affected relatives, unaffected relatives, pedigree, familial genotypes, or meioses are documented. Therefore, cosegregation of NM_001015877.1:c.859G>C with a compatible phenotype cannot be evaluated.

Rule

Generic ACMG/AMP 2015 PP1: cosegregation with disease in multiple affected family members; strength may be increased only with sufficient informative meioses under an applicable validated framework.

Evidence considered

• The case-evidence bundle provides no familial segregation data for NM_001015877.1:c.859G>C.
• PP1 requires cosegregation in affected family members with a disease-consistent phenotype; no informative meioses are available.
• Generic ACMG/AMP fallback is applicable because no PHF6-specific VCEP/CSPEC framework was retrieved.

Still missing

• Pedigree and number of informative meioses
• Phenotype status of relatives
• Genotypes of affected and unaffected relatives
• Phenotype specificity and assessment consistency across relatives

Sources

Reasoning

PP2 requires the gene to have a low rate of benign missense variation and missense to be a common mechanism of disease. No PHF6 CSPEC/VCEP framework is available to specify this gene's missense/benign-rate profile. The pvs1_gene_context establishes germline loss-of-function as a supported PHF6 disease mechanism (Borjeson-Forssman-Lehmann syndrome), but this addresses LOF/truncating mechanism, not specifically the population-level benign missense rate needed to satisfy PP2. No missense constraint metric (e.g., gnomAD missense Z-score/O:E ratio) is present anywhere in the bundle to confirm intolerance to missense variation.

Evidence considered

• pvs1_gene_context.json: lof_mechanism_supported true, mechanism_rationale describing PHF6 loss-of-function as a supported germline disease mechanism, but this does not establish a quantified benign missense rate required for PP2 in the absence of a gene-specific framework

Still missing

• No PHF6-specific missense constraint metric (missense Z-score, O:E ratio) present in the bundle
• No CSPEC/VCEP statement on PHF6 missense benign rate or PP2 applicability
• pvs1_gene_context supports LOF as a disease mechanism generally but does not directly quantify benign missense variation rate needed for PP2

Sources

Reasoning

The case bundle does not provide the patient's phenotype or a phenotype-specific diagnostic assessment. Gene-level descriptions of Borjeson-Forssman-Lehmann syndrome are insufficient to establish that this patient's phenotype is highly specific for the associated disorder.

Rule

Generic ACMG/AMP PP4 requires a patient's phenotype or highly specific disease features to be highly specific for a disease; gene-level disease knowledge alone is insufficient.

Evidence considered

• The case-evidence bundle contains no patient phenotype summary and no applicable VCEP/CSPEC framework for PHF6.

Still missing

• Patient-level phenotype and clinical diagnostic information are unavailable.
• No validated phenotype specificity rule or gene-specific PP4 specification is available.

Reasoning

The case bundle contains no phenotype-annotated healthy adult carriers, no documented unaffected hemizygous males or heterozygous females, and no valid homozygote observations. gnomAD-Canada reports homozygote count 0, but this does not establish the BS2 observation of unaffected individuals and is accompanied by AN=0.

Rule

Generic ACMG/AMP BS2: observation of the variant in healthy adults or in a homozygous state in a recessive disorder; no applicable PHF6-specific VCEP rule was available.

Evidence considered

• The bundle provides no unaffected-carrier phenotype data for NM_001015877.1:c.859G>C.
• The gnomAD-Canada summary lists hom=0 but also AN=0; this cannot be interpreted as a valid homozygote observation or as evidence of unaffected carriers.
• Because PHF6 is X-linked, a BS2 assessment would also require appropriately interpreted hemizygous male and heterozygous female observations, which are not provided.

Still missing

• No clinical cohort or population record documents unaffected adult carriers of this exact variant.
• No valid, adequately powered homozygote or hemizygote observation is available for assessment of the X-linked context.
• No penetrance or age-of-onset information is available for unaffected carriers.

Sources

Reasoning

As with PS3, no validated functional assay data showing normal/wild-type-like activity for NP_001015877.1:p.(Gly287Arg) was located anywhere in the evidence bundle. There is no VCEP-approved assay framework for PHF6 to calibrate assay strength, no PMIDs surfaced by the literature pass, and OncoKB provided only gene-level (not variant-specific) narrative with an 'Unknown Oncogenic Effect' call rather than any functional readout, so it cannot be used to support or refute BS3.

Evidence considered

• literature_pass.json: total_pmids=0, no functional-study PMIDs identified for this variant.
• OncoKB result explicitly not variant-specific and provides no assay readout usable for BS3 calibration.

Still missing

• No functional assay result (of any direction) for this specific variant was found in the case evidence bundle.
• A targeted literature search for functional/rescue-assay characterization of PHF6 p.(Gly287Arg) has not yet been performed and should precede a final not_met call.

Reasoning

No familial phenotype or genotype information is available. The case bundle does not document unaffected relatives who carry the variant, so lack of cosegregation cannot be established.

Rule

Generic ACMG/AMP 2015 BS4: lack of segregation in affected family members; apply only when informative familial genotype and phenotype data demonstrate non-segregation.

Evidence considered

• The case-evidence bundle contains no family history, relative genotypes, or non-segregation observations.
• BS4 requires observation of the variant in affected-unrelated or unaffected family members in a manner inconsistent with disease segregation; no such observation is documented.
• Generic ACMG/AMP fallback is applicable because no PHF6-specific VCEP/CSPEC framework was retrieved.

Still missing

• Pedigree and informative relatives
• Genotypes of unaffected relatives
• Reliable phenotype assessment and age-related penetrance considerations
• Evidence that relatives are informative for the relevant disease

Sources

Reasoning

BP1 requires the gene to be one where missense variants are not a common mechanism of disease (i.e., a predominantly truncating/LOF-mechanism gene where missense is generally benign). The bundle indicates germline PHF6 loss-of-function is a supported disease mechanism (pvs1_gene_context), which could argue against BP1 if missense variants are also established as pathogenic via LOF-equivalent effects (protein destabilization), but no PHF6 CSPEC/VCEP framework or quantified missense benign-rate data is present to make this determination with confidence.

Evidence considered

• pvs1_gene_context.json: mechanism_rationale supporting PHF6 loss-of-function (including missense-driven protein loss, per BFLS mouse-model and patient-derived cell literature summarized for PVS1) as a disease mechanism, suggesting missense variants can be pathogenic in PHF6, but no quantified benign missense rate is available to confidently apply or exclude BP1

Still missing

• No PHF6-specific CSPEC/VCEP guidance on BP1 applicability
• No missense constraint or benign missense rate data present in the bundle
• No literature-derived quantification of missense vs. truncating pathogenic variant proportions for PHF6

Sources

Reasoning

No individual-level observations document this variant in trans with a pathogenic variant in a recessive disorder or in cis with a pathogenic variant in a dominant disorder. The case bundle also provides no phase, affected-status, or inheritance information, so BP2 cannot be assessed.

Rule

Generic ACMG/AMP BP2: consider evidence when the variant is observed in trans with a pathogenic variant in a recessive disorder or in cis with a pathogenic variant in a dominant disorder; phase and disease context must be established.

Evidence considered

• The governing framework record reports no PHF6-specific VCEP/CSPEC specification, so generic ACMG/AMP fallback was used.
• The consolidated case-evidence bundle contains no family, affected-proband, allelic, phase, or inheritance observations relevant to BP2.

Still missing

• No observed genotype context involving a second pathogenic variant is available.
• Phase (trans/cis) is not documented.
• Disease inheritance mode and affected-status context are not documented.

Sources

Reasoning

No patient phenotype, alternate molecular diagnosis, or variant-specific evidence showing that another molecular cause explains the phenotype was provided. BP5 therefore cannot be assessed.

Rule

Generic ACMG/AMP BP5 requires a molecular diagnosis that explains the patient's phenotype and supports an alternative cause; absence of such information is insufficient for assessment.

Evidence considered

• The consolidated case-evidence bundle does not document an alternate molecular diagnosis or variant-specific BP5 evidence.

Still missing

• Patient phenotype and diagnostic workup are unavailable.
• No confirmed alternate molecular diagnosis explaining the phenotype is documented.