PALB2 c.2945G>T, p.(Gly982Val)

Reasoning

NM_024675.4:c.2945G>T is a single-nucleotide substitution in exon 9 of the MANE Select transcript NM_024675.4 predicted to produce the missense change p.(Gly982Val) (NP_078951.2). PVS1 applies only to null variants (nonsense, frameshift, canonical +/-1,2 splice sites, initiation codon, single/multi-exon deletion) per the PALB2 HBOC VCEP v1.2 PVS1 Decision Tree and the SVI PVS1 framework; a missense substitution is not a null-variant consequence and cannot enter the decision tree. SpliceAI reports a max delta score of 0.003, so there is no predicted splice-mediated loss of function. The variant creates no premature termination codon, so NMD is not engaged, and no protein truncation or length change occurs. PVS1 is therefore not applicable for this variant (equivalent to not met).

Rule

Use PALB2 PVS1 Decision Tree (ClinGen HBOC VCEP PALB2 v1.2); the generic SVI null-variant definition covers nonsense, frameshift, canonical +/-1,2 splice, initiation codon, and single/multi-exon deletions only.

Evidence considered

• Variant consequence: NM_024675.4:c.2945G>T is a missense substitution p.(Gly982Val) in PALB2 exon 9 (VariantValidator, MANE Select transcript NM_024675.4; protein NP_078951.2).
• pvs1_variant_assessment records consequence_class 'missense', canonical_splice_consensus false, variant_bucket 'other', and states the variant does not fall into the generic PVS1 null-variant buckets (nonsense, frameshift, canonical +/-1,2 splice).
• PALB2 HBOC VCEP v1.2 (cspec) makes PVS1 applicable only through the PALB2 PVS1 Decision Tree, whose scope is presumed loss-of-function/null and splice variants; a missense substitution is outside that scope.
• pvs1_gene_context confirms germline loss of function is an established disease mechanism for PALB2 (PVS1 gene gate eligible), which is a necessary background condition but does not make a missense variant a null variant.
• SpliceAI max delta score 0.003 (DS_AG 0.002, DS_DG 0.003) indicates no predicted splice impact, excluding splice-mediated loss of function.
• The SVI PVS1 framework (pvs1_generic_framework, PMC6185798; Abou Tayoun et al. 2018, PMID 30192042) defines PVS1 for null-variant consequence types; no such consequence is present here.

Sources

Reasoning

The governing ClinGen HBOC VCEP PALB2 v1.2 CSPEC marks PS1 as applicable only to splicing variants via the PALB2 PS1 splicing table and explicitly directs 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' NM_024675.4:c.2945G>T is a missense change (p.(Gly982Val), exon 9) with no predicted splice impact (SpliceAI max delta score 0.003), so no PS1 splicing-table scenario is triggered. Independently, no previously established pathogenic variant producing the same amino acid change (p.Gly982Val) exists in the collected sources (ClinVar: variant absent; literature_pass identified no PMIDs). PS1 is therefore not applicable to this variant.

Rule

Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2. Splicing: See PALB2 PS1 Table (PMID: 37352859).

Evidence considered

• ClinGen HBOC VCEP PALB2 v1.2 (cspec) PS1 instructions: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2. Splicing: See PALB2 PS1 Table (PMID: 37352859)'; PS1 strength rules (Strong/Moderate/Supporting) all reference the PALB2 PS1 splicing table.
• SpliceAI lookup for NM_024675.4:c.2945G>T reports max delta score 0.003 (DS_AG 0.002, DS_DG 0.003), i.e., no significant predicted splice impact, so no PS1 splicing-table scenario is triggered.
• ClinVar search for PALB2 c.2945G>T returned no result (variant absent from ClinVar); literature_pass.json reports total_pmids = 0, so no previously established pathogenic variant at this residue is available in this case.

Still missing

• No established pathogenic variant producing the same amino acid change p.Gly982Val (e.g., a different nucleotide change at codon 982) is recorded in any collected source; the PALB2 PS1 splicing table itself (PMID 37352859) was not available for review, though it only governs splicing variants.

Sources

Reasoning

The governing framework (ClinGen HBOP Expert Panel PALB2 specification v1.2, cspec doc 1526222356) explicitly marks PS2 as Not applicable for both AD and AR disease: informative de novo occurrences have not yet been observed for PALB2-related autosomal dominant cancer predisposition, and breast cancer occurs frequently as an apparently sporadic event so de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified; for AR disease, de novo occurrences are too rare to be informative and confirmed trans phase via parental testing is impractical. No proband or parental-testing data is present in this case in any event, and no external reports exist (variant absent from ClinVar; no literature PMIDs). Per the VCEP instruction 'Do not use for AD or AR disease', PS2 is not applied.

VCEP rule

VCEP: Not applicable - 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed'

Evidence considered

• Governing framework is the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Expert Panel specification for PALB2 version 1.2 (source_registry key cspec), which takes precedence over generic ACMG/AMP for this gene.
• The PALB2 VCEP marks PS2 as Not applicable with the instruction: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.'
• Consistent with the VCEP applicability ruling, PS2 is not applied to this variant even though no de novo or parental-testing observations exist in the case.
• The case bundle contains no proband phenotype, parental-testing, or family-history section, so there is no de novo observation to evaluate; this is moot given the VCEP not-applicable ruling.

Sources

Reasoning

The governing ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOPC) Expert Panel Specification for PALB2 version 1.2 (cspec doc 1526222356) explicitly declares PS3 'Not Applicable' and defines no PS3 rule, so PS3 is not used in this framework and cannot contribute evidence here. Independently, even under the generic ACMG/AMP framework PS3 would require well-established functional studies demonstrating a deleterious effect for this exact variant; no such data exist in this case bundle: the literature pass returned 0 PMIDs, paper_extracts.json and fulltext_map.json are empty, and OncoKB reports no variant-specific reviewed functional evidence for PALB2 G982V (Unknown Oncogenic Effect, gene-level context only). In silico predictors (SpliceAI max delta 0.003; REVEL 0.158) are not functional assays and were not used as PS3 evidence.

Evidence considered

• ClinGen HBOPC PALB2 VCEP v1.2 lists PS3 applicability as 'Not Applicable'; no PS3 rule is defined in the governing specification
• OncoKB reports 'Unknown Oncogenic Effect' and states it did not identify variant-specific reviewed functional evidence for PALB2 G982V; only gene-level context (PALB2 scaffolding protein involved in DNA repair) is provided
• The case bundle contains no functional assay results for NM_024675.4:c.2945G>T: literature_pass total_pmids = 0, paper_extracts.json = {}, fulltext_map.json = {}
• SpliceAI (max delta 0.003) and REVEL (0.158) are in silico predictions, not well-established functional assays, and cannot satisfy PS3 under generic ACMG/AMP (Richards et al. 2015)

Still missing

• No variant-specific functional assay data for p.(Gly982Val) (e.g., PALB2 homology-directed repair / DNA-damage response assays, FA-N complementation assays, or other validated PALB2 functional assays) are present in the case bundle
• No PMIDs were identified by the literature pass, so no functional study could be reviewed for this variant

Sources

Reasoning

vcep_materials.json domain_tables is empty for PALB2, so no VCEP-approved critical functional domain table exists to check residue Gly982 against (nothing to contradict the VCEP's own applicability designation). The governing ClinGen HBOC VCEP PALB2 v1.2 CSPEC explicitly marks PM1 'Not applicable' with the instruction 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' The variant p.(Gly982Val) is a missense change and does not fall in a statistically significant cancer hotspot (CancerHotspots.org query for PALB2 G982 returned no result). PM1 is therefore not applicable under the governing framework.

VCEP rule

Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.

Evidence considered

• vcep_materials.json domain_tables is empty for PALB2; per pipeline convention an empty domain_tables means no authoritative VCEP domain table was extracted for this gene.
• ClinGen HBOC VCEP PALB2 v1.2 (cspec) PM1 applicability: 'Not applicable'; instruction: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' All PM1 strength rules are marked Not applicable.
• CancerHotspots.org query for 'PALB2 G982' returned no result; the variant is not in a statistically significant cancer hotspot (evidence.json, hotspots result).

Still missing

• vcep_materials.json contains no PALB2 domain_tables entry (key present but empty), so PM1 was decided on the VCEP's explicit not-applicable designation rather than by domain-boundary analysis.

Sources

Reasoning

PM4 addresses protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. The PALB2 HBOC VCEP v1.2 specification explicitly marks PM4 'Not applicable' with the instruction 'Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.' The variant is a missense substitution (p.Gly982Val) that preserves the reading frame and protein length (no in-frame indel, no stop-loss); PM4 is therefore not applicable.

VCEP rule

PM4 not applicable: 'Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.'

Evidence considered

• PALB2 HBOC VCEP v1.2 (cspec) declares PM4 'Not applicable' and restricts its use to stop-loss variants only; in-frame insertions/deletions smaller than a single exon are not to be used.
• Variant consequence is a single-amino-acid substitution p.(Gly982Val): protein length is unchanged (NP_078951.2, Gly->Val at position 982), with no in-frame insertion/deletion and no stop-loss at the termination codon.
• SpliceAI max delta score 0.003 shows no predicted splice impact, so no in-frame exon-level splice event is implicated.

Sources

Reasoning

Under the governing ClinGen HBOC VCEP PALB2 v1.2 CSPEC, PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183 (and NMD-prone splice variants where PVS1_VS(RNA) is applied), and the instructions explicitly state 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' c.2945G>T is a missense change (p.(Gly982Val)) with no predicted splice impact, so it is outside the scope of the VCEP's PM5 rule. Consistent with this, the pm5_candidates artifact reports mode 'truncation_cutoff_gene_specific', eligible_for_classic_pm5_search = false, recommendation level 'not_applicable', and zero same-residue candidate variants.

Rule

Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2. Supporting: Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.

Evidence considered

• ClinGen HBOC VCEP PALB2 v1.2 (cspec) PM5 instructions: 'Based on location of the most C-terminal known pathogenic variant, p.Tyr1183*. Use as PM5_Supporting (not moderate). Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' Supporting rule: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183. Apply to splice variants as with premature termination codons upstream of p.Tyr1183 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone.'
• pm5_candidates.json summary: pm5_mode = 'truncation_cutoff_gene_specific', eligible_for_classic_pm5_search = false, recommendation level = 'not_applicable' ('PM5 is a truncation-cutoff or non-missense framework rule rather than classic same-residue missense PM5'), total_candidates_seen = 0, same_residue_candidates = 0.

Still missing

• No same-residue missense comparator variants (other amino acid substitutions at Gly982) were collected in this case (pm5_candidates: total_candidates_seen = 0, same_residue_candidates = 0), so classic same-residue PM5 could not be evaluated even under a generic framework.

Sources

Reasoning

The governing framework (ClinGen HBOP Expert Panel PALB2 specification v1.2, cspec doc 1526222356) explicitly marks PM6 as Not applicable: informative de novo occurrences have not yet been observed for PALB2 AD disease, and de novo AR (Fanconi anemia) occurrences are too rare to be informative by phase. Per the VCEP instruction 'Do not use for AD or AR disease', PM6 is not applied.

VCEP rule

VCEP: Not applicable - 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase'

Evidence considered

• The PALB2 VCEP marks PM6 as Not applicable with the instruction: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.'
• Consistent with the VCEP applicability ruling, PM6 (assumed de novo without confirmation of paternity/maternity) is not applied to this variant.
• No parental-testing or phase data exists in the case bundle, which is moot given the VCEP not-applicable ruling.

Sources

Reasoning

The governing ClinGen HBOC VCEP PALB2 v1.2 CSPEC marks PP2 'Not applicable' with the instruction 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' PP2 therefore cannot be applied to this missense variant (p.(Gly982Val)).

VCEP rule

Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.

Evidence considered

• ClinGen HBOC VCEP PALB2 v1.2 (cspec) PP2 applicability: 'Not applicable'; instruction: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' All PP2 strength rules are marked Not applicable.

Sources

Reasoning

The governing ClinGen HBOPC VCEP PALB2 v1.2 specification (cspec) explicitly declares PP4 'Not Applicable' (applicability field), so phenotype specificity is not used as an independent criterion for PALB2 variant classification under this specification. The generic ACMG/AMP PP4 rule is therefore not invoked.

VCEP rule

Not Applicable - ClinGen HBOPC VCEP PALB2 v1.2 (cspec)

Evidence considered

• ClinGen HBOPC VCEP PALB2 v1.2 (cspec) lists PP4 with applicability 'Not Applicable', removing phenotype-specificity from the PALB2 criteria set.
• No phenotype-specificity evidence (e.g., variant observed only in affected individuals with a highly specific phenotype) was available in the evidence bundle in any case.

Sources

Reasoning

Two independent reasons: (1) the governing ClinGen HBOPC VCEP PALB2 v1.2 specification (cspec) declares PP5 'Not Applicable'; and (2) PP5 may only be triggered by an exact-variant ClinVar expert-panel classification of Pathogenic/Likely Pathogenic, and this variant is absent from ClinVar entirely (no variation ID, no submissions, no review status), so no expert-panel classification exists to trigger PP5 even under the global PP5 policy. Ordinary laboratory submissions and aggregate labels are explicitly excluded and none exist here.

VCEP rule

Not Applicable - ClinGen HBOPC VCEP PALB2 v1.2 (cspec); no exact-variant ClinVar expert-panel classification exists

Evidence considered

• ClinGen HBOPC VCEP PALB2 v1.2 (cspec) lists PP5 with applicability 'Not Applicable'.
• evidence.json ClinVar lookup found no record: 'This variant is absent from ClinVar' (variation_ids=[], submissions=[], review_status=''), so there is no expert-panel (e.g., HBOPC VCEP) classification for c.2945G>T to support PP5; the only permitted PP5 trigger (exact-variant ClinVar expert-panel Pathogenic/Likely Pathogenic) is absent.

Still missing

• Variant c.2945G>T is absent from ClinVar; an exact-variant ClinVar expert-panel classification (3-star) of Pathogenic/Likely Pathogenic would be required for PP5 to ever apply.

Sources

Reasoning

The governing ClinGen HBOPC PALB2 VCEP v1.2 specification (cspec doc 1526222356) explicitly declares BS3 'Not Applicable' and defines no BS3 rule, so BS3 is not used in this framework. Independently, no assay evidence demonstrating absence of a damaging effect exists for p.(Gly982Val): there are no functional assay results in the case bundle (0 PMIDs, empty paper_extracts and fulltext_map), and OncoKB provides no variant-specific functional assessment. Absence from gnomAD is a population-frequency observation, not a functional assay, and cannot be used to conclude normal protein function. Thus BS3 could not be met under any framework.

Evidence considered

• ClinGen HBOPC PALB2 VCEP v1.2 lists BS3 applicability as 'Not Applicable'; no BS3 rule is defined in the governing specification
• No variant-specific functional data are available for this variant; OncoKB identifies no variant-specific functional evidence (Unknown Oncogenic Effect)
• Variant absence in gnomAD v2.1/v4.1/Canada is a frequency observation and was not treated as functional evidence for BS3
• Under generic ACMG/AMP, BS3 requires well-established functional studies showing no damaging effect (Richards et al. 2015), which are absent here

Still missing

• No validated functional assay showing normal function for p.(Gly982Val) (e.g., homology-directed repair proficiency, BRCA2/PALB2 interaction, FA-N complementation) is available
• No literature was retrieved for this variant that could support a benign functional effect

Sources

Reasoning

The governing ClinGen HBOPC PALB2 VCEP specification v1.2 (cspec) explicitly marks BP2 as 'Not Applicable' for PALB2, so the criterion is not used in this framework and no generic-ACMG fallback is permitted. The VCEP framework supersedes generic ACMG/AMP for PALB2, and this gene-specific determination is applied as-is regardless of the (also absent) generic ACMG data.

VCEP rule

BP2: Not Applicable (PALB2 VCEP v1.2)

Evidence considered

• PALB2 VCEP (ClinGen HBOPC, cspec doc 1526222356, version 1.2) lists BP2 with applicability 'Not Applicable', removing the criterion from consideration for PALB2 variants
• Generic ACMG BP2 (variant in cis with a pathogenic variant, or in trans with a pathogenic variant in a fully penetrant recessive disorder) is not applied because the applicable gene-specific framework declares BP2 not applicable

Sources

Reasoning

BP3 addresses in-frame deletions/insertions in a repetitive region without a known function. The PALB2 HBOC VCEP v1.2 specification explicitly marks BP3 'Not applicable': 'Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function.' The variant is a missense substitution, not an in-frame indel, and no repeat-region context is involved; BP3 is therefore not applicable.

VCEP rule

BP3 not applicable: 'Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function.'

Evidence considered

• PALB2 HBOC VCEP v1.2 (cspec) declares BP3 'Not applicable' because small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2 and PALB2 is not considered to have repetitive regions without known function.
• Variant consequence is a missense substitution (p.Gly982Val) rather than an in-frame deletion/insertion, so the repetitive-region in-frame indel scenario BP3 was designed for does not arise.
• SpliceAI max delta score 0.003 indicates no predicted splice impact, excluding a splice-based in-frame change.

Sources

Reasoning

The governing PALB2 VCEP v1.2 BP4 rule (cspec doc 1526222356) states 'Missense: Do not use' (published predictors have yet to achieve functional outcome for PALB2 missense variants) and 'Splicing: No predicted impact via splicing (SpliceAI <=0.1). Do not apply for missense variants.' Because c.2945G>T is a missense variant (p.(Gly982Val)), BP4 is explicitly not applicable on either the missense-predictor sub-path or the splice sub-path. Although SpliceAI max delta 0.003 would numerically satisfy the <=0.1 splice threshold and REVEL 0.158 falls within the generic ClinGen SVI BP4_Moderate band (PMID 36413997), the governing VCEP forbids BP4 for missense variants, so BP4 is not applied and cannot contribute benign evidence here.

Evidence considered

• PALB2 VCEP v1.2 BP4 rule: 'Missense: Do not use. Splicing: No predicted impact via splicing (SpliceAI <=0.1). Do not apply for missense variants.' c.2945G>T is missense (p.(Gly982Val)), so BP4 is explicitly excluded for this variant class (cspec doc 1526222356)
• SpliceAI max delta = 0.003 would satisfy the VCEP splice-based BP4 threshold (<=0.1), but the VCEP explicitly forbids applying BP4 to missense variants, so BP4 is not applied
• REVEL score 0.158: under the ClinGen SVI REVEL calibration (PMID 36413997) this score falls in the 0.016-0.184 BP4_Moderate band, but the governing PALB2 VCEP instructs 'Missense: Do not use' for BP4, so the score is not applied
• BayesDel score -0.366285 was not applied: no verified published threshold for BP4 is available to this pipeline (insufficiently calibrated)

Still missing

• No RNA functional data are available in the case bundle; under the VCEP, splice-based BP4 is in any case not applied to missense variants
• The VCEP does not provide calibrated missense predictor thresholds for BP4 for PALB2, so no missense-path BP4 evaluation is possible under this framework

Sources

Reasoning

The governing ClinGen HBOPC VCEP PALB2 v1.2 specification (cspec) explicitly declares BP5 'Not Applicable'. The generic ACMG/AMP BP5 rule (variant found in a case with an alternate molecular basis for disease) is therefore not invoked for PALB2. No evidence of an alternate molecular diagnosis was present in the bundle in any case.

VCEP rule

Not Applicable - ClinGen HBOPC VCEP PALB2 v1.2 (cspec)

Evidence considered

• ClinGen HBOPC VCEP PALB2 v1.2 (cspec) lists BP5 with applicability 'Not Applicable'.
• No evidence of an alternate molecular basis of disease in a carrier of this variant was identified anywhere in the evidence bundle.

Sources

Reasoning

Two independent reasons: (1) the governing ClinGen HBOPC VCEP PALB2 v1.2 specification (cspec) declares BP6 'Not Applicable'; and (2) BP6 may only be triggered by an exact-variant ClinVar expert-panel classification of Benign/Likely Benign, and this variant is absent from ClinVar entirely (no variation ID, no submissions, no review status), so no expert-panel classification exists to trigger BP6 even under the global BP6 policy. Ordinary laboratory submissions and aggregate labels are explicitly excluded and none exist here.

VCEP rule

Not Applicable - ClinGen HBOPC VCEP PALB2 v1.2 (cspec); no exact-variant ClinVar expert-panel classification exists

Evidence considered

• ClinGen HBOPC VCEP PALB2 v1.2 (cspec) lists BP6 with applicability 'Not Applicable'.
• evidence.json ClinVar lookup found no record: 'This variant is absent from ClinVar' (variation_ids=[], submissions=[], review_status=''), so there is no expert-panel classification for c.2945G>T to support BP6; the only permitted BP6 trigger (exact-variant ClinVar expert-panel Benign/Likely Benign) is absent.

Still missing

• Variant c.2945G>T is absent from ClinVar; an exact-variant ClinVar expert-panel classification (3-star) of Benign/Likely Benign would be required for BP6 to ever apply.

Sources

Reasoning

The governing PALB2 VCEP v1.2 BP7 rule (cspec doc 1526222356) applies BP7 to synonymous variants and to deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively; the BP7(RNA) sub-rule requires an observed lack of aberrant RNA defect for silent substitutions and intronic variants. c.2945G>T is a missense variant (p.(Gly982Val)) in exon 9, not a synonymous or intronic variant, so neither the position-based BP7 rule nor the RNA-based BP7(RNA) sub-rule applies. No RNA functional data are present in the case bundle. BP7 is therefore not applicable.

Evidence considered

• PALB2 VCEP v1.2 BP7 rule: 'BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively'; BP7(RNA) applies to observed lack of aberrant RNA defect for silent substitutions and intronic variants (cspec doc 1526222356)
• NM_024675.4:c.2945G>T is a missense variant (NP_078951.2:p.(Gly982Val)) in exon 9, so the variant class is outside the scope of the BP7 rule
• The case bundle contains no RNA assay results (literature_pass total_pmids = 0, paper_extracts.json = {}, fulltext_map.json = {})

Still missing

• No RNA functional studies (patient RNA or minigene assays demonstrating lack of aberrant splicing) are available, so the BP7(RNA) sub-rules could not be evaluated
• Variant is missense rather than synonymous/deep intronic, so the position-based BP7 rule does not apply regardless of RNA data

Sources