SETBP1 c.1150A>G, p.(Arg384Gly)

Reasoning

No ClinGen VCEP or gene-specific PP3/BP4 lookup spreadsheet is available for SETBP1; generic ACMG fallback calibrated evidence applies. REVEL score = 0.061 for this missense variant is well below the ClinGen SVI/Pejaver et al. 2022 (PMID 36413997) benign-supporting REVEL threshold, supporting a benign missense prediction. This is corroborated by SpliceAI, which predicts negligible splice impact (max delta 0.012, all donor/acceptor gain/loss scores <=0.012), consistent with no splice-disruptive effect. Both computational lines of evidence concordantly point away from pathogenicity. BayesDel score (-0.401701) is available but excluded because no verified published calibration threshold is available to this pipeline for BayesDel; it is not used to increase strength beyond supporting. BP4 is applied at supporting strength based on the REVEL missense prediction, with SpliceAI as corroborating (not separately counted) evidence of no splice impact.

Rule

generic_acmg_fallback (no SETBP1 VCEP cspec/PP3-BP4 lookup material present)

Evidence considered

• REVEL score = 0.061 for NM_015559.2:c.1150A>G (p.Arg384Gly), below the ClinGen SVI/Pejaver et al. 2022 (PMID 36413997) benign-supporting REVEL cutoff, supporting BP4.
• SpliceAI max delta score = 0.012 (evidence.json evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).') corroborates absence of splice impact; used as supporting context for the same BP4 call, not counted as a second independent criterion instance.
• BayesDel score -0.401701 retrieved but not used for BP4 strength: no named/citable published calibration threshold available to this pipeline for BayesDel.

Sources

Reasoning

No ClinGen SETBP1 VCEP specification exists, so generic ACMG PM1 (mutational hotspot / well-characterized functional domain without benign variation) applies. A targeted CancerHotspots.org query for 'SETBP1 R384' returned no_result / found=false, with the evidence sentence explicitly stating the variant 'does not lie in a statistically significant hotspot.' Gene-level context (NCBI Gene summary and OncoKB gene background) describes SETBP1's known germline/somatic mutational hotspot as a narrow SKI-homology-region degron motif recognized by the SCF-beta-TrCP E3 ubiquitin ligase, a cluster distinct from residue 384; no domain/hotspot annotation in the case bundle places Arg384 within that degron or any other characterized critical domain. There is no evidence supporting PM1 for this residue.

Rule

generic_ACMG_PM1_no_hotspot_or_domain_hit

Evidence considered

• CancerHotspots.org query for 'SETBP1 R384' returned no_result (found=false); evidence sentence: 'This variant does not lie in a statistically significant hotspot.' (screenshot: hotspots.png)
• OncoKB gene background (queried via oncokb source, page load ultimately failed for variant-specific page) and NCBI Gene summary both describe the known SETBP1 mutational hotspot as residing in a degron motif within the SKI-homology region recognized by the SCF-beta-TrCP E3 ubiquitin ligase complex, which is not annotated as overlapping residue 384.

Still missing

• No dedicated residue-level SETBP1 domain map (e.g., exact degron boundary coordinates) was retrieved in this case's artifacts; if a future source places residue 384 within a structurally or functionally critical domain, this call should be revisited.

Reasoning

PM2 is not met. Although the global gnomAD v4.1 AF is 0.009850%, the relevant highest ancestry-specific AF is 0.166879% in South Asians (grpmax FAF 0.145219%), exceeding the generic PM2 rarity threshold of 0.1%.

Rule

Generic ACMG/AMP population-frequency fallback: PM2 requires absence or a highest credible ancestry-specific frequency below 0.1% when no applicable gene-specific specification is available.

Evidence considered

• No SETBP1 ClinGen CSPEC/VCEP or local gene-specific framework was retrieved; generic population-frequency thresholds were used.
• gnomAD v4.1 reports South Asian AF 0.166879% (152/91,084 alleles) and grpmax FAF 0.145219%, despite a lower global AF of 0.009850%.
• gnomAD v2.1 independently reports South Asian AF 0.160183% and grpmax FAF 0.124468%.
• Using only the global AF would be a threshold artifact: the replicated ancestry-specific frequency, not the diluted global frequency, governs PM2 rarity assessment.

Sources

Reasoning

No ClinGen VCEP or gene-specific PP3/BP4 lookup material is available for SETBP1 (vcep_materials.json: no cspec url available, framework falls back to generic_acmg). Under generic calibrated computational evidence: SpliceAI max delta score = 0.012 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.012), far below any threshold associated with predicted splice disruption, so the splice-impact path does not support PP3. For the missense path, REVEL score = 0.061, far below the ClinGen SVI-calibrated pathogenic-supporting threshold (REVEL >=0.644, Pejaver et al. 2022, PMID 36413997), so REVEL does not support PP3 either. BayesDel score (-0.401701) is available but this pipeline has no verified published calibration threshold for BayesDel, so it is treated as not_available and not used to score PP3. No line of calibrated in-silico evidence supports a pathogenic effect; PP3 is not met.

Rule

generic_acmg_fallback (no SETBP1 VCEP cspec/PP3-BP4 lookup material present)

Evidence considered

• SpliceAI max delta score = 0.012 (DS_AG=0.0, DS_AL=0.0, DS_DG=0.0, DS_DL=0.012); evidence.json evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).'
• REVEL score = 0.061, well below the ClinGen SVI/Pejaver et al. 2022 (PMID 36413997) pathogenic-supporting REVEL cutoff of 0.644, so it does not meet the threshold to support PP3.
• BayesDel score -0.401701 was retrieved but excluded from scoring: no verified published calibration threshold for BayesDel is available to this pipeline.

Sources

Reasoning

The exact ClinVar record has no expert-panel submissions; therefore, no expert-panel Pathogenic or Likely pathogenic assertion is available to support PP5.

Rule

Apply PP5 only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• ClinVar variation 1579051 exactly matches SETBP1 c.1150A>G (p.Arg384Gly), but its two submissions are from clinical laboratories and the submission audit reports zero expert-panel submissions.

Sources

Reasoning

BA1 is not met. The highest robust population estimate is the gnomAD v4.1 South Asian AF of 0.166879% (152/91,084 alleles; grpmax FAF 0.145219%), far below the generic 1% BA1 threshold.

Rule

Generic ACMG/AMP population-frequency fallback: BA1 requires allele frequency at or above 1% when no applicable gene-specific specification is available.

Evidence considered

• No SETBP1 ClinGen CSPEC/VCEP or local gene-specific framework was retrieved; generic population-frequency thresholds were used.
• gnomAD v4.1 reports total AF 0.009850% (159/1,614,138 alleles), South Asian AF 0.166879% (152/91,084 alleles), and South Asian grpmax FAF 0.145219%; no homozygotes were observed.
• gnomAD v2.1 independently reports South Asian AF 0.160183% (49/30,590 alleles) and grpmax FAF 0.124468%; no homozygotes were observed.
• The observed South Asian enrichment is replicated across gnomAD releases and remains well below 1%; it is not a BA1 threshold artifact.

Sources

Reasoning

BS1 is not met. The maximum observed South Asian AF is 0.166879% in gnomAD v4.1, with grpmax FAF 0.145219%; both are below the generic 0.3% BS1 threshold.

Rule

Generic ACMG/AMP population-frequency fallback: BS1 requires allele frequency above 0.3% when no applicable gene-specific specification is available.

Evidence considered

• No SETBP1 ClinGen CSPEC/VCEP or local gene-specific framework was retrieved; generic population-frequency thresholds were used.
• gnomAD v4.1 South Asian AF is 0.166879% (152/91,084 alleles), and its grpmax FAF is 0.145219%.
• gnomAD v2.1 South Asian AF is 0.160183% (49/30,590 alleles), with grpmax FAF 0.124468%.
• The modest South Asian enrichment is consistent between releases but does not exceed the 0.3% BS1 threshold.

Sources

Reasoning

The exact ClinVar record has no expert-panel submissions; the reported Likely benign assertions are ordinary laboratory submissions and cannot support BP6.

Rule

Apply BP6 only to an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• ClinVar variation 1579051 exactly matches SETBP1 c.1150A>G (p.Arg384Gly). PreventionGenetics and Labcorp submitted Likely benign assertions, but both are non-expert clinical laboratory submissions and the audit reports zero expert-panel submissions.

Sources

Reasoning

No ClinGen SETBP1 VCEP specification exists (cspec.found=false; gene_vcep_dir=null; framework_mode=generic_acmg). PS1 requires identification of a different nucleotide change producing the identical amino-acid change, p.(Arg384Gly), previously established as pathogenic. No PS1 comparator search or candidate list was collected for this case (pm5_candidates.json only covers alternate-residue comparators and was itself marked ineligible), and no source in the bundle reports another variant resulting in the same p.Arg384Gly substitution.

Still missing

• No same-amino-acid-change (PS1) comparator search was performed or returned in this case's evidence artifacts; a dedicated ClinVar/literature search for other NM_015559.2 c.1150 substitutions and any confirmed pathogenic p.(Arg384Gly)-equivalent call is needed before this criterion can be assessed.

Reasoning

No case-level parental genotypes, parentage confirmation, proband phenotype, or de novo testing result is provided for NM_015559.2:c.1150A>G (p.Arg384Gly).

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo occurrence in a patient with a phenotype consistent with the relevant disease and with maternity and paternity confirmed.

Evidence considered

• No SETBP1 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated bundle contains no proband-level, parental-genotype, parentage, or de novo evidence for this variant.

Still missing

• Obtain proband phenotype and diagnosis information.
• Obtain parental testing results for the exact variant, including confirmation of biological parentage when available.

Reasoning

No ClinGen VCEP-specific framework exists for SETBP1 (cspec not found; framework_mode = generic_acmg, precedence_rank 3, generic ACMG/AMP fallback applies). No functional/biochemical assay data (in vitro, in vivo, cell-based, or biochemical activity studies) for NM_015559.2:c.1150A>G (p.Arg384Gly) were identified in the case evidence bundle. The only literature hit is PMID:28492532 (Sherloc), a variant classification methodology paper flagged as background_review theme with no candidate criteria and no variant-specific functional content; it does not report a validated assay result for this variant. No publications directory content was retrieved for full-text review since no functional-themed paper was triaged. Absent any validated assay evidence, PS3 cannot be assessed.

Evidence considered

• literature_pass.json lists only one PMID (28492532, Sherloc classification methodology paper) with theme 'background_review' and no candidate_criteria; it is not a functional assay study of this variant.
• case_summary.json cspec.found = false; vcep_materials.json note = 'no cspec url available', confirming no SETBP1 VCEP functional-assay specification exists for this case.
• No functional assay data fields present anywhere in evidence.json for this variant.

Still missing

• No functional/biochemical assay publication for NM_015559.2:c.1150A>G identified in literature_pass.json or evidence.json
• No gene-specific (VCEP) functional assay framework available for SETBP1 to calibrate assay validity or strength

Reasoning

No case-control, cohort-enrichment, or statistically interpretable affected-versus-control data for SETBP1 c.1150A>G (p.Arg384Gly) were retrieved.

Rule

Generic ACMG/AMP PS4: prevalence in affected individuals must be significantly increased compared with controls.

Evidence considered

• No PS4-relevant publications were triaged; the only retrieved PMID is a general ACMG/AMP framework article rather than variant case evidence.

Still missing

• Variant-specific case counts in a defined SETBP1-related phenotype cohort and an appropriate control comparison are required.

Reasoning

No qualifying affected-proband observation of NM_015559.2:c.1150A>G with a pathogenic/likely pathogenic SETBP1 variant in trans is provided. The case bundle contains no second germline variant, phase result, segregation information, phenotype, or recessive disease assignment.

Rule

Generic ACMG/AMP PM3: requires an affected individual with the variant in trans with a pathogenic variant for a recessive disorder.

Evidence considered

• No SETBP1 VCEP/ClinGen CSPEC or local gene-specific framework was retrieved; the bundle designates generic ACMG/AMP fallback.
• The ClinVar record is an exact variant match but supplies only two likely-benign germline submissions and no co-occurring-variant, phase, affected-proband, or pedigree evidence. Its final classification was not used to infer this criterion.
• The consolidated bundle provides no additional patient-level allelic observation or phase evidence.

Still missing

• Affected-proband genotype and phenotype data.
• A confirmed pathogenic/likely pathogenic second SETBP1 allele, with molecular phase demonstrating trans configuration.
• Disease-specific inheritance mode applicable to the proband.

Sources

Reasoning

The case's dedicated pm5_candidates.json artifact explicitly declined to run the automatic same-residue candidate harvest: pm5_mode='unknown', eligible_for_classic_pm5_search=false, candidate_summary shows 0 total/same-residue candidates collected, and its own recommendation states 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting' with an instruction not to apply PM5 from that artifact alone. No other source in the bundle lists a different missense substitution at codon 384 with an established pathogenic classification.

Evidence considered

• pm5_candidates.json: pm5_mode='unknown', eligible_for_classic_pm5_search=false, reason='Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting', candidates=[] (0 same-residue candidates found), recommendation.level='not_applicable'.

Still missing

• A manual ClinVar/literature search for other pathogenic or likely pathogenic missense substitutions at SETBP1 codon 384 (e.g., p.Arg384*, p.Arg384Trp, p.Arg384Gln) has not been completed for this case; pm5_candidates.json explicitly flagged this gap and recommended against auto-applying PM5.

Sources

Reasoning

No case-level parental testing result documents an assumed de novo occurrence of NM_015559.2:c.1150A>G (p.Arg384Gly).

Rule

Generic ACMG/AMP PM6 requires an assumed de novo occurrence without confirmation of maternity and paternity in a patient with a phenotype consistent with the relevant disease.

Evidence considered

• No SETBP1 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated bundle contains no proband-level, parental-genotype, parentage, or de novo evidence for this variant.

Still missing

• Obtain parental testing results for the exact variant.
• Obtain proband phenotype and diagnosis information to assess consistency with a SETBP1-related disorder.

Reasoning

No informative family pedigree, genotype data in affected or unaffected relatives, phenotype data, or count of segregation events is provided for NM_015559.2:c.1150A>G (p.Arg384Gly).

Rule

Generic ACMG/AMP PP1 requires co-segregation of the variant with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• No SETBP1 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated bundle contains no family segregation or meiosis evidence for this variant.

Still missing

• Obtain a pedigree with phenotypes and genotypes for informative affected and unaffected relatives.
• Provide the number of informative meioses and the family-specific disease model.

Reasoning

No ClinGen SETBP1 VCEP specification exists, so generic ACMG PP2 (missense variant in a gene with a low rate of benign missense variation and where missense is a common disease mechanism) would apply if data were available. SETBP1's germline disease mechanism is mixed/atypical: the pvs1_gene_context.json literature review supports SETBP1 loss-of-function as a germline disease mechanism (ADR29/SETBP1 haploinsufficiency disorder from truncating variants), while a separate, narrow degron-hotspot missense mechanism drives classic Schinzel-Giedion syndrome via impaired protein degradation. No missense constraint metric (e.g., gnomAD missense Z-score/o:e ratio) or ClinGen-curated benign-missense-rate statement for SETBP1 was captured anywhere in this case's evidence bundle, so the quantitative basis PP2 requires (low benign missense tolerance) cannot be evaluated.

Evidence considered

• pvs1_gene_context.json mechanism_rationale: targeted germline literature review supports SETBP1 loss-of-function as a germline disease mechanism (autosomal dominant mental retardation 29 / SETBP1-HD), while OncoKB/NCBI Gene background separately describe a distinct narrow degron-motif missense hotspot mechanism driving Schinzel-Giedion syndrome, indicating a mixed truncating/missense disease mechanism across the gene rather than missense being uniformly the primary mechanism.

Still missing

• No gnomAD constraint metrics (missense Z-score, missense o/e ratio) or a gene-specific statement on rate of benign missense variation for SETBP1 were retrieved in this case's evidence artifacts; this is required to determine whether SETBP1 meets the low-benign-missense-rate criterion for PP2.

Reasoning

No phenotype for the tested individual and no variant-specific clinical report were provided, so phenotype specificity for a SETBP1-related disorder cannot be evaluated.

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 retrieved evidence bundle contains no proband phenotype data or variant-specific phenotype publication.

Still missing

• Detailed proband phenotype, onset, and differential diagnosis information are required to assess whether the presentation is highly specific for a SETBP1-related condition.

Reasoning

BS2 cannot be assessed from the available evidence. gnomAD reports no homozygotes, and the population dataset does not establish that any observed carriers are well phenotyped unaffected adults for a SETBP1-related disorder.

Rule

Generic ACMG/AMP BS2: observe the variant in a healthy adult individual for a disorder expected to be fully penetrant early in life; do not infer unaffected status from unphenotyped population controls.

Evidence considered

• gnomAD v4.1 records zero homozygotes among 159 alternate alleles, including zero South Asian homozygotes among 152 alternate alleles.
• gnomAD v2.1 records zero homozygotes among 49 alternate alleles.
• Absence of homozygotes is not BS2 evidence; BS2 requires observation in sufficiently informative unaffected individuals.

Still missing

• Age and phenotype data for heterozygous carriers are unavailable.
• No observation of the variant in an individual whose unaffected status is informative for the relevant SETBP1 phenotype was provided.

Sources

Reasoning

No ClinGen VCEP-specific framework exists for SETBP1 (cspec not found; generic ACMG/AMP fallback applies, precedence_rank 3). No functional/biochemical assay data showing normal/wild-type-like activity for NM_015559.2:c.1150A>G (p.Arg384Gly) were identified. The single literature hit, PMID:28492532 (Sherloc), is a general classification methodology paper (background_review theme) with no candidate_criteria and no reported assay result for this specific variant. Without a validated functional assay demonstrating normal protein function, BS3 cannot be assessed.

Evidence considered

• literature_pass.json lists only one PMID (28492532, Sherloc classification methodology paper) with theme 'background_review' and no candidate_criteria; it is not a functional assay study of this variant.
• case_summary.json cspec.found = false; vcep_materials.json note = 'no cspec url available', confirming no SETBP1 VCEP functional-assay specification exists for this case.
• No functional assay data fields present anywhere in evidence.json for this variant.

Still missing

• No functional/biochemical assay publication for NM_015559.2:c.1150A>G identified in literature_pass.json or evidence.json
• No gene-specific (VCEP) functional assay framework available for SETBP1 to calibrate assay validity or strength

Reasoning

No informative evidence shows that NM_015559.2:c.1150A>G (p.Arg384Gly) fails to segregate with a relevant SETBP1-related phenotype in a family.

Rule

Generic ACMG/AMP BS4 requires lack of segregation of the variant with disease in affected family members.

Evidence considered

• No SETBP1 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated bundle contains no family non-segregation evidence for this variant.

Still missing

• Obtain genotype and phenotype data for informative relatives, including unaffected carriers or affected non-carriers where age-dependent penetrance and phenocopies have been considered.

Reasoning

No ClinGen SETBP1 VCEP specification exists, so generic ACMG BP1 (missense in a gene where primarily truncating variants are known to cause disease) would apply if data were available. Germline SETBP1 disease is mechanistically heterogeneous: pvs1_gene_context.json supports a loss-of-function (truncating-driven) mechanism for one germline phenotype (ADR29/SETBP1-HD), but Schinzel-Giedion syndrome is caused specifically by missense variants clustered in a narrow degron hotspot, meaning missense variants are also a well-established, non-truncating germline disease mechanism for this gene. This mixed mechanism precludes a clean 'primarily truncating' BP1 determination, and no quantitative statement (e.g., proportion of truncating vs. missense pathogenic variants) was captured in this case's evidence bundle to support or refute BP1.

Evidence considered

• pvs1_gene_context.json and NCBI Gene/OncoKB gene summaries jointly indicate SETBP1 germline disease mechanism is heterogeneous, spanning both loss-of-function truncating variants (ADR29/SETBP1-HD) and a well-characterized missense degron-hotspot mechanism (Schinzel-Giedion syndrome), precluding a 'primarily truncating' determination without further quantitative data.

Still missing

• No quantitative breakdown of truncating-versus-missense pathogenic variant proportions for SETBP1 germline disease was retrieved in this case's evidence artifacts, which is needed to determine whether the gene meets the 'primarily truncating' pattern required for BP1.

Reasoning

No observation of NM_015559.2:c.1150A>G in cis with a pathogenic/likely pathogenic SETBP1 variant, or in trans with such a variant for a dominant disorder, is provided. Consequently, BP2 cannot be assessed.

Rule

Generic ACMG/AMP BP2: requires the variant to be observed in cis with a pathogenic variant, or in trans with a pathogenic variant for a fully penetrant dominant disorder.

Evidence considered

• No SETBP1 VCEP/ClinGen CSPEC or local gene-specific framework was retrieved; the bundle designates generic ACMG/AMP fallback.
• The ClinVar record is an exact variant match but supplies no co-occurring-variant, phase, affected-proband, or pedigree evidence. Its final classification was not used to infer this criterion.
• The consolidated bundle provides no additional patient-level allelic observation or phase evidence.

Still missing

• A confirmed pathogenic/likely pathogenic co-occurring SETBP1 variant.
• Molecular phase demonstrating cis configuration, or trans configuration together with the applicable dominant disease model.
• Associated phenotype and inheritance information for the individual carrying both variants.

Sources

Reasoning

No case-level molecular diagnostic information was retrieved showing an alternate pathogenic cause that fully explains a reported phenotype in a carrier of this variant.

Rule

Generic ACMG/AMP BP5: the variant is found in a case with an alternate molecular basis for disease.

Evidence considered

• No variant-specific case report or diagnostic workup was available in the evidence bundle.

Still missing

• Case-level phenotype and concurrent molecular findings are required to determine whether an alternate diagnosis fully explains the phenotype.