Frequently Asked Questions

What file formats does Folklore accept?

Primary variant analysis accepts single-sample VCF 4.1 or 4.2 files in plain-text (.vcf) or bgzipped (.vcf.gz) form. Multi-sample files should be split before upload. Family analysis combines separately processed proband, parent, and sibling samples.

Which genome builds are supported?

GRCh38 (hg38) is the primary build. GRCh37 (hg19) files are accepted and automatically lifted over to GRCh38 using CrossMap. Earlier builds are not supported.

How long does analysis take?

Processing time depends on file size, enabled modules, variant count, and server load. Panel and exome files usually complete faster than whole-genome files. The processing record shows the actual duration for each stage and case.

Where is patient data stored?

All data is processed and stored on EU-based infrastructure in Helsinki, Finland (Hetzner AX162R dedicated server). No patient data is transmitted to external services, cloud providers, or AI APIs.

Is patient data deleted after analysis?

Yes. VCF files and analysis results are retained only for the duration needed for clinical review. Data deletion policies comply with GDPR requirements.

Which ACMG criteria are automated?

Folklore computes criteria that can be derived from the submitted variants, reference databases, phenotype data, and supported family context. Evidence that depends on functional studies, case-control data, or expert assessment remains available for clinical curation. The Criteria Reference documents the status of each criterion.

What computational predictor is used for PP3/BP4?

BayesDel_noAF with ClinGen SVI-calibrated thresholds (Pejaver et al. 2022). The "_noAF" variant excludes allele frequency from its model to avoid circular reasoning with PM2, BA1, and BS1. SpliceAI is used independently for splice impact (PP3_splice).

Does Folklore support structural variants, CNVs, and mitochondrial variants?

Yes. Folklore interprets compatible structural-variant calls already present in the VCF; it does not perform upstream SV calling. Constitutional copy-number loss and gain use the Riggs 2020 framework, while other eligible nuclear structural events can enter the nuclear Variant Analysis framework. Mitochondrial variants use MMDWG 2020. Repeat expansions and somatic tumor variants remain outside these modules.

Does the platform support somatic variant interpretation?

No. Folklore is designed for germline variant interpretation in Mendelian disease contexts. Somatic variant analysis requires tumor-normal paired analysis with different classification frameworks (AMP/ASCO/CAP).

What databases are used for annotation?

The core Stage 4 enrichment uses 16 production classification and reference databases, including gnomAD v4.1, ClinVar 2025-01, dbNSFP 4.9c, SpliceAI, HPO, ClinGen, and Ensembl VEP Release 113. Across nuclear, phenotype, inheritance, mitochondrial, and SV/CNV modules, Folklore integrates 45 total reference databases and curated sources. Smaller counts in subsystem descriptions refer to selected source sets, not the platform-wide total. Production reference data is stored locally.

How does phenotype matching work?

Patient HPO terms are compared against gene-phenotype associations using Lin semantic similarity within the HPO ontology graph. Genes are ranked by the strength of phenotype correlation and assigned clinical priority tiers. See the Phenotype Matching documentation for details.

What does the AI clinical assistant use for its model?

A large language model hosted on dedicated GPU infrastructure within the EU. All inference happens on-premise through a secure internal connection. No patient data is sent to external AI services.

Can the AI assistant modify variant classifications?

No. ACMG classifications are determined by the automated pipeline. The AI assistant can explain why criteria were triggered and discuss the evidence, but it cannot change classifications. Only the reviewing geneticist can override classifications.

Is the clinical interpretation a medical diagnosis?

No. The AI-generated clinical interpretation is a decision support tool. All findings must be independently validated by a qualified clinical geneticist before being used in patient care. Reports include a standard disclaimer stating this requirement.

How often are reference databases updated?

ClinVar is updated quarterly or more frequently for clinically significant changes. gnomAD major releases are adopted within 3 months of publication. All updates undergo validation testing with a reference cohort before deployment. See the Database Update Policy for the complete schedule.

Can I use Folklore for research purposes?

Yes. The platform is suitable for both clinical and research use. For research applications, the same analytical rigor applies but reporting requirements may differ from clinical diagnostic settings.

What happens if ClinVar and the automated classification disagree?

Folklore applies a transparent priority system: BA1 always overrides ClinVar, expert-panel ClinVar assertions can override the automated classification, and conflicting evidence is flagged for manual review. See the ClinVar Integration documentation for the complete decision logic.