c.3647A>G

Reasoning

PVS1 cannot be assessed because the submitted HGVS expression has a reference-base mismatch, leaving the transcript, gene, variant consequence, exon position, and NMD prediction unresolved. In addition, loss of function as a disease mechanism has not been established for the unidentified gene.

Rule

Generic ClinGen SVI PVS1 framework: do not assign PVS1 without a resolved predicted loss-of-function consequence and evidence that loss of function is a disease mechanism for the relevant gene.

Evidence considered

• VariantValidator reported that the submitted reference base A does not agree with the NM_000264.5 reference sequence, which has G at c.3647; no normalized transcript or protein consequence was produced.
• The available gene-level PVS1 context identifies no gene and leaves germline loss-of-function eligibility unresolved, with manual review required.
• The ClinGen SVI PVS1 framework is the applicable generic consequence framework, but the case artifact states that it cannot be applied until gene-level loss-of-function eligibility and variant consequence are resolved.

Still missing

• Resolve or correct NM_000264.5:c.3647A>G against the transcript reference sequence.
• Establish the affected gene's germline disease association and whether loss of function is an established disease mechanism.
• After normalization, assess consequence, exon position, and whether a premature termination event would be subject to NMD or remove a critical region.

Sources

Reasoning

PS1 requires the variant to produce the same amino-acid change as a previously established pathogenic variant (regardless of nucleotide change). This cannot be evaluated: normalization of NM_000264.5:c.3647A>G failed (VariantValidator ReferenceMismatchError: the reference base at c.3647 is G, not A as submitted), so no gene symbol, genomic coordinates, predicted protein consequence, or affected residue were established (protein_1l/protein_3l null; hgvs_predicted_protein_consequence empty). ClinVar retrieval was skipped ('no gene'), source_registry contains no ClinVar/PMID entries, literature_pass.json reports 0 PMIDs, and no established-pathogenic comparator of any kind is present in the case bundle. The governing framework is the generic ACMG/AMP 2015 fallback (no CSPEC/VCEP present), under which PS1 cannot be applied to an unconfirmed variant with an unknown residue. Returned not_assessed rather than not_met because the absence of data reflects a failed normalization, not evidence that the criterion's premise is false.

Evidence considered

• Governing framework is the generic ACMG/AMP 2015 fallback (framework_mode 'generic_acmg', final_classification_framework precedence_rank 3, scoring_model 'ACMG/AMP 2015', PMID 25741868); no ClinGen CSPEC or gene-specific VCEP materials exist for this case (cspec skipped 'no gene', vcep_materials domain_tables empty).
• prefetch.json normalization: VariantValidator returned ReferenceMismatchError 'Variant reference (A) does not agree with reference sequence (G)' for NM_000264.5:c.3647A>G with 1 LOVD-suggested correction; extracted gene '', genomic coordinates null, predicted protein consequence empty.
• case_summary.json: ClinVar block empty (variation_ids [], classification null, no PMIDs); literature_pass.json total_pmids 0 ('No PMIDs found across evidence sources'); no source in the case bundle reports any previously established pathogenic variant at this residue.

Still missing

• Corrected/confirmed HGVS notation needed: the submitted A>G allele conflicts with the transcript reference (G at c.3647); the true change may be c.3647G>A, may belong to a different transcript version, or may not exist in NM_000264.5
• Once normalized: confirmed protein consequence and affected amino-acid residue
• ClinVar/literature records of the same amino-acid change classified pathogenic by an expert panel or multiple submitters

Sources

Reasoning

No usable proband-level de novo observation or documented parental testing is present. Variant normalization failed because the submitted reference allele did not match the available transcript sequence, leaving gene and genomic coordinates unresolved; the evidence bundle contains no case-level family data.

Rule

PS2 requires a confirmed de novo occurrence in a patient with the relevant phenotype and confirmed maternity and paternity; strength may be calibrated when an applicable specification provides sufficient confirmed de novo observations.

Evidence considered

• The governing framework indicates that no VCEP or gene-specific specification was retrieved, so generic ACMG/AMP fallback was used.
• The case bundle reports VariantValidator ReferenceMismatchError for NM_000264.5:c.3647A>G and states that normalization is incomplete; gene and coordinates are unavailable.
• The case bundle contains no proband, parental testing, maternity/paternity, or de novo family evidence.

Still missing

• Confirm the variant identity and transcript normalization.
• Provide proband phenotype and genotype details.
• Provide confirmed maternity and paternity and parental testing results showing the variant absent in both tested parents.

Sources

Reasoning

No validated functional assay evidence is available in the case bundle. Variant normalization failed because the submitted reference allele did not match the reference sequence, leaving the gene and consequence unresolved; no VCEP-specific framework, functional-study publications, or paper findings were retrieved. PS3 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS3 requires well-established functional studies supportive of a damaging effect; no assay evidence is available here.

Evidence considered

• The bundle reports no applicable VCEP materials and falls back to generic ACMG/AMP rules.
• The bundle reports zero literature PMIDs and an empty paper_extracts object, so no functional assay publication was available for review.
• Normalization was incomplete: NM_000264.5:c.3647A>G produced a reference-mismatch warning, with gene, coordinates, and consequence unresolved.

Still missing

• Resolve the variant identity and consequence from a valid HGVS description.
• Identify any applicable gene-specific VCEP functional-assay rules.
• Retrieve and evaluate validated functional studies with appropriate controls and biologically relevant assay endpoints.

Sources

Reasoning

Case-control enrichment cannot be assessed because the submitted HGVS could not be normalized, leaving no resolved gene, genomic coordinate, or exact variant record; no case-control data were retrieved.

Rule

Generic ACMG/AMP PS4: increased prevalence in affected individuals compared with controls requires variant-specific case-control evidence.

Evidence considered

• VariantValidator reported that the submitted reference allele A does not agree with the transcript reference sequence G at NM_000264.5:c.3647.
• The evidence bundle contains no retrieved PMIDs, phenotype cases, or case-control datasets.

Still missing

• Resolve the reference-allele mismatch and normalize the variant.
• Obtain variant-specific affected and control allele counts or a validated case-control enrichment study.

Reasoning

PM1 requires the variant to lie in a mutational hot spot and/or a critical, well-established functional domain. Per the governing instructions, vcep_materials.json domain_tables is the authoritative domain list when an entry exists for the gene; here domain_tables is empty ({}) with no CSPEC URL available, and no gene or residue was identified (normalization failed: reference-allele mismatch at c.3647; protein consequence empty), so no residue-to-domain mapping is possible under either a VCEP table or the generic ACMG/AMP 2015 fallback. No ClinGen domain-table or hotspot evidence is present in any bundle file (hotspots.source_data empty, evidence.json results empty). Returned not_assessed: the variant's residue itself is unestablished, so absence of a domain entry cannot be equated with the variant being outside all critical domains.

Evidence considered

• vcep_materials.json: note 'no cspec url available', final_classification_framework found false (generic ACMG/AMP 2015 fallback), domain_tables {} — no authoritative critical-functional-domain table exists for this case's gene, and the gene itself was never resolved.
• prefetch.json normalization failed (VariantValidator ReferenceMismatchError at c.3647; gene '', coords null), so the variant's protein residue could not be determined and no domain-overlap check could be performed.
• evidence.json/hotspots data are empty (found null, source_data {}), providing no hot-spot or domain placement evidence.

Still missing

• Corrected/confirmed HGVS notation and the resulting gene symbol and amino-acid residue
• A governing VCEP/CSPEC domain table for the gene (vcep_materials domain_tables currently empty) or a generic-framework basis for a well-established critical functional domain/hot spot
• Review of whether the residue falls in any known functional domain once the gene is identified

Sources

Reasoning

PM2 was not assessed because normalization failed and no validated population database result established absence or rarity of the variant in an appropriate reference population.

Rule

not_assessed_pending_variant_normalization_and_validated_population_lookup; no applicable VCEP-specific rule was retrieved

Evidence considered

• VariantValidator reported a reference mismatch for NM_000264.5:c.3647A>G and the case has no resolved gene or genomic coordinates.
• The case bundle reports no gnomAD v2.1, gnomAD v4.1, gnomAD Canada, or other population-frequency result; therefore absence cannot be distinguished from a failed lookup.
• No VCEP/gene-specific framework was retrieved; the generic framework artifact does not provide a case-specific PM2 rule or threshold.

Still missing

• Resolve the HGVS reference mismatch and obtain the correct gene, transcript, and genomic coordinates.
• Retrieve population data from an appropriate dataset, including coverage and ancestry context, and evaluate absence/rarity under the applicable generic or gene-specific PM2 rule.

Sources

Reasoning

PM3 could not be assessed because variant normalization failed: the supplied NM_000264.5:c.3647A>G has a reference-sequence mismatch, no gene or genomic coordinates were resolved, and no affected-proband, phase, inheritance, or trans/cis observations are available in the case evidence bundle.

Rule

Generic ACMG/AMP PM3 requires well-established observation of the variant in trans with a pathogenic variant (or appropriate recessive disease allelic evidence); no such evidence is available for this unresolved variant.

Evidence considered

• The case summary reports framework_mode as generic_acmg because no gene-specific VCEP/CSPEC framework was available.
• The prefetch record reports ReferenceMismatchError for NM_000264.5:c.3647A>G and states that normalization is incomplete; gene and genomic coordinates are unresolved.
• The consolidated evidence bundle contains no case-level allelic observations, no ClinVar submissions, no literature PMIDs, and no paper extracts relevant to PM3.

Still missing

• Resolve the HGVS reference mismatch and confirm the intended variant and gene.
• Obtain case-level observations identifying affected probands and the disease-associated phenotype.
• Establish whether the variant is in trans with a pathogenic or likely pathogenic variant, including phasing evidence and inheritance information.

Reasoning

PM4 cannot be assessed because the variant did not normalize and there is no established protein consequence or protein length change. The submitted transcript-level substitution cannot be treated as an in-frame length-changing variant while the reference-base mismatch remains unresolved.

Rule

Generic ACMG/AMP PM4: evaluate only a confirmed protein length-changing variant, with repeat-region context considered to avoid overlap with BP3.

Evidence considered

• VariantValidator reported a reference-base mismatch for NM_000264.5:c.3647A>G and returned no normalized transcript, gene, variant class, or protein consequence.
• The case evidence contains no protein-length, exon, domain, or repeat-region annotation for this unresolved variant.

Still missing

• Resolve or correct the submitted HGVS expression.
• Determine the resulting protein consequence and whether it is an in-frame deletion/insertion or stop-loss that changes protein length.
• If a length-changing consequence is confirmed, assess whether it lies in a repetitive region before applying PM4.

Reasoning

PM5 requires a novel missense change at a residue where a different missense change has already been established as pathogenic. The PM5 candidate artifact could not support this: pm5_candidates.json reports pm5_mode 'unknown', eligible_for_classic_pm5_search false ('Unable to confirm classic same-residue PM5 semantics safely'), residue context unparsed (reference_aa/position/observed_alt_aa all null), and 0 candidates of any kind. ClinVar retrieval was skipped ('no gene') and literature_pass.json contains 0 PMIDs, so no same-residue pathogenic comparator is available. Returned not_assessed pending confirmation of the variant's residue and a same-residue comparator search.

Evidence considered

• pm5_candidates.json: candidate_summary total_candidates_seen 0, same_residue_candidates 0, expert_panel_plp_candidates 0, conflicted_candidates 0; recommendation level 'not_applicable', instructing that PM5 must not be applied from this artifact alone and that same-residue comparators need human review.
• case_summary.json: ClinVar block empty and pm5_candidates_summary pm5_mode 'unknown' (eligible_for_classic_pm5_search false); no ClinVar submissions or PMIDs exist anywhere in the case bundle.
• Governing framework is the generic ACMG/AMP 2015 fallback (PMID 25741868) since no gene-specific PM5 specification is available.

Still missing

• Confirmed amino-acid residue (requires corrected variant notation and successful normalization)
• ClinVar/literature search for different missense changes at the same residue that are established pathogenic (expert-panel or multiple-submitter classifications), which was skipped because no gene could be resolved
• Human review of whether any collected same-residue comparator satisfies the governing PM5 rule (artifact recommendation level 'not_applicable')

Sources

Reasoning

No case-level report of an apparently de novo variant without confirmed parental testing is present. The variant itself is not reliably normalized, and the bundle contains no proband, phenotype, or family report from which PM6 could be evaluated.

Rule

PM6 may be considered for an apparently de novo occurrence when maternity and paternity are not confirmed, but it requires credible case-level evidence and is weaker than confirmed de novo evidence.

Evidence considered

• The governing framework indicates that no VCEP or gene-specific specification was retrieved, so generic ACMG/AMP fallback was used.
• The case bundle reports failed normalization and no resolved gene or coordinates.
• The case bundle contains no literature PMIDs, paper extracts, proband report, or parental-testing information supporting an assumed de novo event.

Still missing

• Confirm the variant identity and transcript normalization.
• Provide a documented affected proband and phenotype consistent with the suspected disorder.
• Provide the source report and details of the parental testing limitation or absence of parental testing.

Sources

Reasoning

No affected relatives, informative meioses, phase information, or family segregation observations are provided. Therefore cosegregation cannot be assessed.

Rule

PP1 supports pathogenicity when a variant cosegregates with disease in multiple affected family members; strength can be increased only when the number and informativeness of meioses meet an applicable calibrated rule.

Evidence considered

• The governing framework indicates that no VCEP or gene-specific specification was retrieved, so generic ACMG/AMP fallback was used.
• The case bundle contains no pedigree, familial genotype data, segregation observations, or meioses.
• No paper extracts or literature sources are available for family-based segregation evidence.

Still missing

• Provide a pedigree with affected and unaffected relatives.
• Provide genotype results for informative relatives and the number of informative meioses.
• Document phenotype consistency and assess whether the observed segregation exceeds expectations by chance.

Sources

Reasoning

PP2 requires gene-level evidence that the gene has a low rate of benign missense variation and that missense is a common mechanism of disease. Neither premise can be evaluated: the gene was never resolved (normalization failure at c.3647), gnomAD evidence sentences are null in case_summary for v2.1/v4.1/Canada and evidence.json gnomad results are empty, and no gene-specific framework exists. Generic ACMG/AMP 2015 (PMID 25741868) PP2 is therefore not assessable. Returned not_assessed rather than not_met because no gene-level data were retrieved at all.

Evidence considered

• case_summary.json: gnomad v2_1/v4_1/Canada evidence_sentence all null with source_data null; clinvar and literature blocks empty — no benign-variant-rate or mechanism data were retrieved.
• evidence.json: results.gnomad {} and manifest entries ok false; no population or gene-level constraint source is registered in source_registry.json.
• No CSPEC or gene-specific framework is available (framework_mode 'generic_acmg'); generic ACMG/AMP 2015 PP2 (PMID 25741868) cannot be applied without a resolved gene.

Still missing

• Resolved gene symbol (requires corrected HGVS notation / successful normalization)
• Gene-level missense constraint data (e.g., gnomAD observed/expected missense metrics and benign missense rate) for the resolved gene
• Evidence on whether missense is a common mechanism of disease in the resolved gene (gene-specific framework or literature)

Sources

Reasoning

PP3 cannot be assessed because the submitted transcript-level HGVS failed reference-sequence validation, leaving no normalized gene, genomic coordinates, molecular consequence, SpliceAI result, or calibrated missense predictor result.

Evidence considered

• VariantValidator reported that the submitted reference allele A does not agree with the NM_000264.5 reference sequence, which has G at c.3647; normalization therefore produced no gene or genomic coordinates.
• The case evidence contains no SpliceAI score and no REVEL or BayesDel score; REVEL and BayesDel retrieval were skipped because coordinates were unavailable.
• No gene-specific VCEP/ClinGen specification was retrieved because the gene could not be identified.

Still missing

• Resolve the reference mismatch for NM_000264.5:c.3647A>G and normalize the variant to a valid transcript/genomic representation.
• Obtain an applicable gene-specific VCEP specification, if one exists, after gene identification.
• Obtain SpliceAI and, if the resolved variant is missense, a calibrated computational predictor result with a published threshold.

Reasoning

Phenotype specificity cannot be assessed because neither a gene nor patient phenotype/disease context was resolved, and no phenotype literature was retrieved.

Rule

Generic ACMG/AMP PP4: the patient's phenotype or family history must be highly specific for a disease with a single genetic etiology.

Evidence considered

• The normalized case record has an empty gene field and no protein or genomic consequence.
• The literature packet reports no PMIDs and no criterion-screened phenotype evidence.

Still missing

• Resolve the variant to its gene and disease mechanism.
• Provide the proband phenotype and evidence that it is highly specific for the relevant gene-associated disease.

Reasoning

PP5 cannot be applied because no exact-variant ClinVar record or ClinVar expert-panel Pathogenic/Likely pathogenic assertion was retrieved.

Rule

Apply PP5 at supporting strength only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; do not use laboratory submissions, aggregate labels, or non-expert assertions.

Evidence considered

• ClinVar retrieval was skipped because no gene was resolved for the submitted HGVS.
• No ClinVar variation ID, classification, review status, or submissions are present in the case evidence.

Still missing

• Resolve the variant and verify whether ClinVar contains an exact-variant Pathogenic or Likely pathogenic expert-panel assertion.

Reasoning

BA1 was not assessed because the variant could not be normalized: VariantValidator reported a reference mismatch (submitted A, reference G), no gene or genomic coordinates were resolved, and no population-frequency dataset was retrieved.

Rule

not_assessed_pending_variant_normalization_and_population_frequency; no applicable VCEP-specific rule was retrieved

Evidence considered

• The case bundle reports NM_000264.5:c.3647A>G but normalization failed with a VariantValidator ReferenceMismatchError: the submitted reference A does not agree with the reference sequence G.
• The case bundle contains no resolved gene, genomic coordinates, gnomAD v2.1/v4.1/Canada data, or other population-frequency observation for this variant.
• No VCEP or gene-specific framework was retrieved; the case is marked generic_acmg, and the available generic framework artifact does not provide a case-specific BA1 threshold.

Still missing

• Resolve the HGVS reference mismatch and obtain the correct gene, transcript, and genomic coordinates.
• Retrieve a validated population allele frequency and assess whether any applicable ancestry-specific or disease-prevalence threshold is exceeded.

Sources

Reasoning

BS1 was not assessed because the variant identity was not resolved and no population frequency, ancestry-stratified frequency, disease prevalence, or penetrance data were retrieved.

Rule

not_assessed_pending_variant_normalization_and_frequency_threshold; no applicable VCEP-specific rule was retrieved

Evidence considered

• Variant normalization was incomplete because VariantValidator reported that the submitted reference A disagrees with the reference sequence G; gene and coordinates remain unresolved.
• The case bundle shows empty gnomAD v2.1, gnomAD v4.1, and gnomAD Canada evidence, with no alternative population dataset reported.
• No VCEP/gene-specific framework was available, and the generic framework artifact does not supply a disease-specific BS1 threshold for this unresolved variant.

Still missing

• Resolve the HGVS reference mismatch and obtain the correct gene, transcript, and genomic coordinates.
• Retrieve validated population frequencies with ancestry context and compare them with an applicable disease-specific maximum credible frequency or BS1 threshold.

Sources

Reasoning

BS2 was not assessed because no reliable unaffected homozygote or hemizygote observations, phenotype information, inheritance context, disease prevalence, or penetrance assessment were available.

Rule

not_assessed_pending_variant_identity_and_unaffected_genotype_phenotype_data; no applicable VCEP-specific rule was retrieved

Evidence considered

• The case bundle contains no resolved variant coordinates or gene and no clinical or population genotype observations.
• No unaffected homozygote/hemizygote evidence, ancestry information, disease-prevalence estimate, or penetrance information was retrieved.
• No VCEP/gene-specific framework was retrieved; the generic framework artifact does not provide a case-specific BS2 rule.

Still missing

• Resolve the variant identity before evaluating genotype observations.
• Search validated population and clinical datasets for unaffected homozygous or hemizygous individuals and document phenotype, age, inheritance model, and penetrance context.

Sources

Reasoning

No validated functional assay evidence demonstrating a well-established benign effect is available in the case bundle. Variant normalization failed because the submitted reference allele did not match the reference sequence, leaving the gene and consequence unresolved; no VCEP-specific framework, functional-study publications, or paper findings were retrieved. BS3 therefore cannot be assessed.

Rule

Generic ACMG/AMP BS3 requires well-established functional studies showing no damaging effect on protein function or a biologically relevant assay; no assay evidence is available here.

Evidence considered

• The bundle reports no applicable VCEP materials and falls back to generic ACMG/AMP rules.
• The bundle reports zero literature PMIDs and an empty paper_extracts object, so no functional assay publication was available for review.
• Normalization was incomplete: NM_000264.5:c.3647A>G produced a reference-mismatch warning, with gene, coordinates, and consequence unresolved.

Still missing

• Resolve the variant identity and consequence from a valid HGVS description.
• Identify any applicable gene-specific VCEP functional-assay rules.
• Retrieve and evaluate validated functional studies with appropriate controls and biologically relevant assay endpoints demonstrating a benign effect.

Sources

Reasoning

No unaffected informative relatives with reliable genotype and phenotype data are provided. Absence of family data cannot establish non-segregation.

Rule

BS4 supports benignity when a variant does not segregate with disease in affected or expected-to-be-affected informative relatives; an absence of family information is not evidence of non-segregation.

Evidence considered

• The governing framework indicates that no VCEP or gene-specific specification was retrieved, so generic ACMG/AMP fallback was used.
• The case bundle contains no unaffected relatives, pedigree, genotype data, phenotype assessment, or non-segregation observations.
• No paper extracts or literature sources are available for non-segregation evidence.

Still missing

• Provide a pedigree and identify informative unaffected relatives.
• Provide reliable genotype testing for those relatives.
• Confirm that the relatives are expected to be affected based on age, penetrance, phenotype definition, and inheritance model before interpreting non-segregation.

Sources

Reasoning

BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease (i.e., missense is not an established disease mechanism). The gene is unresolved (normalization failed: reference-allele mismatch at c.3647; protein consequence unknown, so even the missense class is unconfirmed), and the gene-mechanism premise is explicitly unresolved: pvs1_gene_context.json reports germline_disease_context_found false, lof_mechanism_supported false, status 'unresolved', with incomplete literature retrieval, and no gene-specific framework exists. Generic ACMG/AMP 2015 (PMID 25741868) BP1 therefore cannot be assessed. Returned not_assessed because neither the variant class nor the gene's truncating-only mechanism could be established.

Evidence considered

• pvs1_gene_context.json: germline_disease_context_found false, lof_mechanism_supported false, pvs1_gene_gate 'manual_review_required', literature_search status 'unresolved' ('Targeted literature retrieval ... did not complete cleanly') — the truncating-vs-missense mechanism premise underlying BP1 is unverifiable from the case bundle.
• prefetch.json: normalization incomplete (VariantValidator ReferenceMismatchError at c.3647; gene '', coding '', residue ''), so the variant cannot even be confirmed as a missense substitution.
• No CSPEC/gene-specific framework exists (vcep_materials empty; generic ACMG/AMP 2015 fallback, PMID 25741868).

Still missing

• Resolved gene symbol and confirmed variant consequence class (missense vs other) from corrected HGVS notation
• Gene mechanism evidence: whether only/primarily truncating variants cause disease in the resolved gene, with literature retrieval completed (pvs1_gene_context status currently 'unresolved')
• A governing gene-specific or generic framework decision on BP1 applicability for the resolved gene

Sources

Reasoning

BP2 could not be assessed because the variant identity and gene remain unresolved and the case evidence bundle contains no observations of the variant in cis or trans with another pathogenic variant, no family segregation data, and no inheritance information.

Rule

Generic ACMG/AMP BP2 requires observation of the variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder, as applicable; no qualifying observation is available.

Evidence considered

• The case summary reports that gene, transcript/protein normalization, coordinates, and ClinVar data are unavailable.
• The prefetch record reports a reference-sequence mismatch and normalization failure for the supplied HGVS expression.
• The consolidated evidence bundle contains no case-level allelic observations, no literature PMIDs, and no paper extracts relevant to BP2.

Still missing

• Resolve the HGVS reference mismatch and confirm the intended variant and gene.
• Determine whether the variant has been observed in cis or trans with a pathogenic or likely pathogenic variant.
• Obtain phase, family, and inheritance data sufficient to evaluate the BP2 context.

Reasoning

BP3 cannot be assessed because the variant did not normalize and there is no evidence of an in-frame protein length change or of localization within a repetitive region without known function.

Rule

Generic ACMG/AMP BP3: evaluate only a confirmed in-frame deletion or insertion in a repetitive region without known function.

Evidence considered

• VariantValidator reported a reference-base mismatch for NM_000264.5:c.3647A>G and returned no normalized transcript, gene, variant class, or protein consequence.
• No gene-specific specification, protein repeat map, or domain table is available in the case evidence.

Still missing

• Resolve or correct the submitted HGVS expression.
• Determine whether the normalized variant produces an in-frame deletion or insertion.
• Obtain repeat-region and functional-region annotation for the affected protein interval.

Reasoning

BP4 cannot be assessed because the submitted HGVS is not validated and no normalized consequence, SpliceAI result, or calibrated benign computational prediction is available.

Evidence considered

• VariantValidator reported that the submitted reference allele A does not agree with the NM_000264.5 reference sequence, which has G at c.3647; normalization therefore produced no gene or genomic coordinates.
• The case evidence contains no SpliceAI score and no REVEL or BayesDel score; REVEL and BayesDel retrieval were skipped because coordinates were unavailable.
• No gene-specific VCEP/ClinGen specification was retrieved because the gene could not be identified.

Still missing

• Resolve the reference mismatch for NM_000264.5:c.3647A>G and normalize the variant to a valid transcript/genomic representation.
• Obtain an applicable gene-specific VCEP specification, if one exists, after gene identification.
• Obtain SpliceAI and, if the resolved variant is missense, a calibrated computational predictor result with a published threshold.

Reasoning

BP5 cannot be assessed because no affected individual, phenotype, or independent molecular diagnosis is available for this unresolved variant.

Rule

Generic ACMG/AMP BP5: a variant may support a benign interpretation when it is found in a case with an alternate molecular basis for disease.

Evidence considered

• No patient-level phenotype, molecular diagnoses, or literature cases were retrieved in the evidence bundle.

Still missing

• Resolve the variant and obtain case-level data documenting an alternate molecular cause that fully explains the phenotype.

Reasoning

BP6 cannot be applied because no exact-variant ClinVar record or ClinVar expert-panel Benign/Likely benign assertion was retrieved.

Rule

Apply BP6 at supporting strength only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; do not use laboratory submissions, aggregate labels, or non-expert assertions.

Evidence considered

• ClinVar retrieval was skipped because no gene was resolved for the submitted HGVS.
• No ClinVar variation ID, classification, review status, or submissions are present in the case evidence.

Still missing

• Resolve the variant and verify whether ClinVar contains an exact-variant Benign or Likely benign expert-panel assertion.

Reasoning

BP7 cannot be assessed because the submitted HGVS fails reference-sequence validation, so it is not possible to establish that the variant is synonymous or to evaluate predicted splice impact.

Evidence considered

• VariantValidator reported that the submitted reference allele A does not agree with the NM_000264.5 reference sequence, which has G at c.3647; no protein consequence or variant class was resolved.
• The case evidence contains no SpliceAI score.
• No gene-specific VCEP/ClinGen specification was retrieved because the gene could not be identified.

Still missing

• Resolve the reference mismatch for NM_000264.5:c.3647A>G and normalize the variant to a valid transcript/genomic representation.
• Confirm whether the resolved variant is synonymous.
• Obtain an applicable gene-specific VCEP specification, if one exists, and a splice-impact prediction for the resolved variant.