tooluniverse-structural-variant-analysis

name

tooluniverse-structural-variant-analysis

description

Comprehensive structural variant (SV) analysis skill for clinical genomics. Classifies SVs (deletions, duplications, inversions, translocations), assesses pathogenicity using ACMG-adapted criteria, evaluates gene disruption and dosage sensitivity, and provides clinical interpretation with evidence grading. Use when analyzing CNVs, large deletions/duplications, chromosomal rearrangements, or any structural variants requiring clinical interpretation.

Structural Variant Analysis Workflow

Systematic analysis of structural variants (deletions, duplications, inversions, translocations, complex rearrangements) for clinical genomics interpretation using ACMG-adapted criteria.

KEY PRINCIPLES:

1. Report-first approach - Create SV_analysis_report.md FIRST, then populate progressively
2. ACMG-style classification - Pathogenic/Likely Pathogenic/VUS/Likely Benign/Benign with explicit evidence
3. Evidence grading - Grade all findings by confidence level (★★★/★★☆/★☆☆)
4. Dosage sensitivity critical - Gene dosage effects drive SV pathogenicity
5. Breakpoint precision matters - Exact gene disruption vs dosage-only effects
6. Population context essential - gnomAD SVs for frequency assessment
7. English-first queries - Always use English terms in tool calls

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Triggers

Use this skill when users:

• Ask about structural variant interpretation or CNV data
• Ask "is this deletion/duplication pathogenic?"
• Need ACMG classification for SVs or gene dosage assessment
• Have chromosomal rearrangements requiring interpretation

NOT for: SNV/indel interpretation → tooluniverse-variant-interpretation; gene enrichment → tooluniverse-gene-enrichment

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Workflow (7 Phases)

Phase 1: SV Identity & Classification

Normalize coordinates (hg19/hg38), determine type (DEL/DUP/INV/TRA/CPX), calculate size, assess breakpoint precision.

SV Type	Abbreviation	Molecular Effect
Deletion	DEL	Haploinsufficiency, gene disruption
Duplication	DUP	Triplosensitivity, dosage imbalance
Inversion	INV	Gene disruption at breakpoints, position effects
Translocation	TRA	Gene fusions, disruption, position effects
Complex	CPX	Variable effects

Phase 2: Gene Content Analysis

Identify genes fully contained in SV and genes with breakpoints (disrupted). Annotate function and disease associations.

Tool	Purpose
Ensembl_lookup_gene	Gene structure, coordinates, exons
NCBI_gene_search	Official symbol, description
OMIM_search + OMIM_get_entry	Disease associations, inheritance
DisGeNET_search_gene	Gene-disease evidence scores
Gene_Ontology_get_term_info	Biological process, molecular function

Phase 3: Dosage Sensitivity Assessment

from tooluniverse import ToolUniverse
tu = ToolUniverse(use_cache=True); tu.load_tools()

# ClinGen dosage (gold standard)
clingen = tu.tools.ClinGen_search_dosage_sensitivity(gene="KANSL1")
# -> hi_score: 3 = Sufficient evidence for HI

# ClinGen gene validity
validity = tu.tools.ClinGen_search_gene_validity(gene="KANSL1")
# -> Classification: Definitive

# gnomAD constraint (pLI)
gnomad = tu.tools.gnomad_get_gene_constraints(gene_symbol="KANSL1")
# -> pLI close to 1.0 = loss-of-function intolerant

# OMIM inheritance
omim = tu.tools.OMIM_search(operation="search", query="KANSL1", limit=3)

Evidence grading: HI/TS score=3 + Definitive validity = ★★★ | Score 2-3 = ★★☆ | Otherwise = ★☆☆

Phase 4: Population Frequency Context

Tool	Purpose
gnomad_search	Population SV frequencies, overlapping SVs
ClinVar_search_variants	Known pathogenic/benign SVs (chromosome, start, stop, variant_type)
DECIPHER_search	Patient SVs with phenotypes, case reports

ACMG frequency codes:

• ≥1% in gnomAD SVs → BA1 (Stand-alone Benign)
• 0.1-1% → BS1 (Strong Benign)
• <0.01% or absent → PM2 (Supporting Pathogenic)

Reciprocal overlap: min(overlap/SV_A_length, overlap/SV_B_length) ≥70% = "same" SV

Phase 5: Pathogenicity Scoring (0-10)

Component	Weight	Max Points
Gene content	40%	4 pts: dosage-sensitive gene disrupted; 3: disease gene fully contained; 2: OMIM gene; 1: any gene
Dosage sensitivity	30%	3 pts: HI/TS score=3 + Definitive validity; 2: score 2-3; 1: predicted only
Population frequency	20%	2 pts: absent from gnomAD+DGV; 1: rare (<0.01%); 0: common
Clinical match	10%	1 pt: phenotype consistent + literature support

Score interpretation:

• 9-10: Pathogenic | 7-8.9: Likely Pathogenic | 4-6.9: VUS | 2-3.9: Likely Benign | 0-1.9: Benign

Phase 6: Literature & Clinical Evidence

Tool	Purpose
PubMed_search_articles	Similar SVs, gene disruption studies (returns plain list)
DECIPHER_search	Developmental disorder cases with overlapping SVs
EuropePMC_search_articles	Broader literature search

Phase 7: ACMG-Adapted Classification

Key pathogenic codes for SVs:

• PVS1: Gene disruption of established HI gene (Very Strong)
• PS1: Same SV as known pathogenic in ClinVar (Strong)
• PS3: Functional studies confirm dosage sensitivity (Strong)
• PM2: Absent from population databases (Moderate)
• PP4: Patient phenotype matches gene's disease (Supporting)

Key benign codes:

• BA1: ≥1% frequency in gnomAD SVs (Stand-alone)
• BS1: 0.1-1% frequency (Strong)
• BP1: No known disease genes in region (Supporting)

Classification: 1 Very Strong + 1 Strong = Pathogenic | 1 Very Strong + 1-2 Moderate = Likely Pathogenic | Contradictory = VUS

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Report Template

Section	Content
1. SV Summary	Type, coordinates, size, breakpoint precision
2. Gene Content	Fully contained genes, disrupted genes, regulatory elements
3. Dosage Sensitivity	ClinGen HI/TS scores, pLI, validity level per gene
4. Population Frequency	gnomAD/ClinVar/DECIPHER overlaps, ACMG codes
5. Pathogenicity Score	0-10 score with component breakdown
6. Literature Evidence	Key publications, DECIPHER cases, functional evidence
7. ACMG Classification	Evidence codes applied, final classification + rationale
8. Clinical Recommendations	Immediate actions, further investigation, genetic counseling

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Extended Reference: Full Python implementations for each phase, detailed ACMG criteria tables, example reports, and edge case handling are in REFERENCE.md.