Reference Databases
Folklore integrates 45 reference databases and curated sources across variant annotation, classification, phenotype matching, screening, inheritance analysis, mitochondrial analysis, and SV/CNV interpretation. These external and curated sources are materialized into internal reference tables and derived views. Production reference data is stored locally on EU-based infrastructure in Helsinki, Finland.
Reference versions are pinned per deployment and recorded through the reference-data manifest. The table below lists selected core sources used by the nuclear germline workflow; it is not the complete inventory of all 45 integrations or of every internal reference table and derived view.
How the database counts are defined
The core Stage 4 enrichment currently loads 16 production classification and reference databases. The platform-wide figure of 45 counts all reference databases and curated sources used across nuclear classification, phenotype, inheritance, screening, mitochondrial, and SV/CNV modules. Smaller numbers in a subsystem, selected-source table, or historical changelog describe that narrower set; they are not alternative totals for the current platform.
Zero External API Calls
Core genomic processing uses locally stored reference data and a local Ensembl VEP cache. Patient variants are not submitted to public genomic databases or third-party annotation APIs during the analysis path.
Database Summary
| Database | Primary Use | ACMG Criteria |
|---|---|---|
| gnomAD | Population frequencies | BA1, BS1, BS2, PM2 |
| ClinVar | Clinical significance | PS1, PP5, BP6, ClinVar override |
| dbNSFP | Functional predictions | PP3, BP4 (BayesDel_noAF) |
| SpliceAI | Splice impact | PP3_splice, BP7 guard |
| gnomAD Constraint | Gene-level tolerance | PVS1, PP2, BP1 |
| HPO | Gene-phenotype mapping | PP4 |
| ClinGen | Dosage sensitivity | BS1, BP2 |
| Orphanet | Gene-disease-inheritance | BS1 (AD/AR/XLD), PVS1 gate |
| VCEP Specs | Gene-specific thresholds | BA1, BS1, PM2, PVS1 gate |
| ClinGen GDV | Gene-disease validity | PVS1 constraint gate, disease association gate |
| DECIPHER G2P | Molecular mechanism curation | PVS1 GoF/DN guard, disease association gate |
| GoFCards | Gain-of-function curation | PVS1 GoF guard |
| Ensembl VEP | Variant effect prediction | PVS1, PM1, PM4, BP1, BP3, BP7 |
Annotation Pipeline
Reference data is loaded into each variant record during Stage 4 of the processing pipeline. After annotation, every variant carries all reference columns directly -- no database lookups are needed during classification or clinical review. The annotation order is:
gnomAD v4.1
Population allele frequencies. Positional match on chromosome, position, reference allele, and alternate allele. Loads 6 columns.
ClinVar
Clinical significance assertions. Same positional match. Loads 7 columns including review stars and disease associations.
dbNSFP 4.9c
Functional predictions from SIFT, AlphaMissense, MetaSVM, DANN, BayesDel, and conservation scores. Loads 9 columns with duplicate variant aggregation.
gnomAD Constraint
Gene-level tolerance metrics. Joined on gene symbol. Loads 4 columns: pLI, LOEUF, o/e LoF, and missense Z-score.
HPO
Gene-phenotype associations. Joined on gene symbol with deduplication and aggregation. Loads 6 columns.
ClinGen
Dosage sensitivity scores. Joined on gene symbol. Loads 2 columns: haploinsufficiency and triplosensitivity.
Ensembl VEP runs as a separate stage (Stage 3) before database annotation, providing consequence predictions and transcript selection that the annotation phases then build upon. SpliceAI scores are accessed from precomputed data during VEP annotation.
In This Section
gnomAD
Population allele frequencies from 807,162 individuals across 8 genetic ancestry groups.
ClinVar
Clinical significance assertions from submitting laboratories worldwide.
dbNSFP
Functional predictions and conservation scores for all possible coding SNVs.
HPO
Gene-phenotype associations from the Human Phenotype Ontology.
ClinGen
Gene dosage sensitivity curation from the Clinical Genome Resource.
Ensembl VEP
Variant Effect Predictor for consequence annotation and transcript selection.
SpliceAI Precomputed
Precomputed splice impact delta scores for all coding variants.
Update Policy
How and when reference databases are updated, validated, and versioned.
SV/CNV Reference Evidence
ClinGen Dosage, dosage regions, and population evidence used by the Riggs workflow.
mtDNA Reference Evidence
Mitochondrial frequencies, haplogroups, predictors, ClinVar assertions, and NUMT flags.
For details on how these databases are combined during ACMG classification, see the Criteria Reference.