genomics-pipeline

Step 5: Structural Variant Annotation (AnnotSV)

What This Does

Classifies every structural variant from Manta using ACMG guidelines (class 1-5), adding gene overlap, population frequency, and clinical significance.

Why

Raw Manta output contains thousands of SVs with no clinical interpretation. AnnotSV tells you which ones matter by cross-referencing known pathogenic SVs, gene databases, and population data.

Tool

• AnnotSV — ACMG-compliant structural variant annotation and classification

Docker Image

getwilds/annotsv:latest

Command

SAMPLE=your_sample
GENOME_DIR=/path/to/your/data

docker run --rm \
  --cpus 4 --memory 8g \
  -v ${GENOME_DIR}:/genome \
  getwilds/annotsv:latest \
  AnnotSV \
    -SVinputFile /genome/${SAMPLE}/manta/results/variants/diploidSV.vcf.gz \
    -genomeBuild GRCh38 \
    -outputFile /genome/${SAMPLE}/annotsv/${SAMPLE}_annotsv \
    -outputDir /genome/${SAMPLE}/annotsv

Output

• ${SAMPLE}_annotsv.tsv — main annotated output (one row per SV, with ACMG class)
• Columns include: SV type, coordinates, overlapping genes, DGV frequency, ACMG classification, ClinVar hits

ACMG Classification

| Class | Meaning | Action | |—|—|—| | 1 | Benign | Ignore | | 2 | Likely benign | Ignore | | 3 | Variant of uncertain significance (VUS) | Review if in known disease gene | | 4 | Likely pathogenic | Investigate — check gene, inheritance, phenotype | | 5 | Pathogenic | Investigate — known disease-causing SV |

Important Notes

• Class 4-5 = pathogenic/likely pathogenic — these require manual review
• SVs >5MB in short-read WGS are usually artifacts from segmental duplications — do not trust large calls blindly
• Most SVs will be class 2-3 (benign/VUS) — this is normal for a healthy genome
• Input must be from Manta step 4 (diploidSV.vcf.gz), not the unfiltered candidates
• AnnotSV bundles its own annotation databases inside the Docker image — no separate download needed

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