ACMG
American College of Medical Genetics and Genomics. Publisher of the 2015 variant classification guidelines used by Folklore.
ACMG Secondary Findings (SF)
A curated list of 81 genes (v3.2) where pathogenic variants should be reported regardless of the primary testing indication, because early identification can lead to medical interventions.
Allele Frequency (AF)
The proportion of a specific allele in a population. Used for BA1 (>5%), BS1, and PM2 (<0.01%) criteria. Sourced from gnomAD.
AlphaMissense
A protein structure-based pathogenicity predictor from DeepMind. Displayed for clinical reference in Folklore but does not contribute to ACMG classification.
BayesDel_noAF
The ClinGen SVI-calibrated computational meta-predictor used by Folklore for PP3 and BP4 ACMG criteria. The "_noAF" suffix indicates allele frequency is excluded from its model.
Benign
ACMG classification for a variant with a Bayesian total of -6 or below, or a valid stand-alone BA1 result.
BP4
Computational benign evidence. For missense variants, Folklore uses the calibrated BayesDel_noAF benign ranges; supported non-canonical splice variants may use the documented SpliceAI benign path.
ClinGen
Clinical Genome Resource. Provides dosage sensitivity scores and gene-specific ACMG classification specifications (VCEP). Funded by NIH.
ClinVar
NCBI database of clinical significance assertions for genetic variants. Folklore uses ClinVar for PS1, PP5, BP6 criteria and classification override.
Compound Heterozygote
Two different heterozygous variants in the same gene that are established or suspected to be in trans. Their clinical significance depends on the variants, gene mechanism, phase, and phenotype.
Confidence Score
A continuous score (0.0-1.0) reflecting how far a variant is from the classification boundary. Higher scores indicate more certain classifications.
Consequence
The predicted effect of a variant on the gene product, determined by Ensembl VEP. Examples: missense_variant, frameshift_variant, splice_donor_variant.
DANN
Deep Annotation of Noncoding Variants. A deep neural network pathogenicity score applicable to any single nucleotide variant. Displayed for reference.
dbNSFP
Database for Nonsynonymous SNPs Functional Predictions. Version 4.9c provides BayesDel, SIFT, AlphaMissense, MetaSVM, DANN, PhyloP, and GERP scores.
DuckDB
An in-process analytical database engine used by Folklore for variant storage and querying. Each analysis session uses an isolated DuckDB file.
Ensembl VEP
Variant Effect Predictor from EMBL-EBI. Determines variant consequences, transcript selection, and functional annotations. Runs locally with offline cache.
GERP
Genomic Evolutionary Rate Profiling. Measures evolutionary constraint at a genomic position. Scores >4.0 indicate strongly constrained sites.
gnomAD
Genome Aggregation Database. Version 4.1 provides population allele frequencies from 807,162 individuals across 8 genetic ancestry groups.
GRCh38
Genome Reference Consortium Human Build 38 (hg38). The current standard human reference genome used by Folklore.
Haploinsufficiency
A condition where loss of one gene copy (one allele) is sufficient to cause disease. ClinGen curates haploinsufficiency scores (0-3).
HGVS
Human Genome Variation Society nomenclature. Standard notation for describing variants at the genomic (g.), coding DNA (c.), and protein (p.) levels.
HPO
Human Phenotype Ontology. A standardized vocabulary of over 17,000 phenotypic abnormalities used for phenotype matching and PP4 criteria.
Impact
VEP-assigned severity category: HIGH (frameshift, stop gained), MODERATE (missense), LOW (synonymous), MODIFIER (intronic, UTR).
Likely Benign
ACMG classification for a Bayesian total from -1 through -5.
Likely Pathogenic
ACMG classification indicating the variant is probably disease-causing. Bayesian points between 6 and 9.
LOEUF
Loss-of-function Observed/Expected Upper bound Fraction. Lower values indicate stronger gene constraint. Values < 0.35 are considered highly constrained.
MetaSVM
A Support Vector Machine meta-predictor combining 10 individual prediction tools. Displayed for clinical reference.
Pathogenic
ACMG classification for a Bayesian total of 10 or more, subject to the applicable priority and conflict rules.
PhyloP
Phylogenetic P-value. Measures evolutionary conservation across 100 vertebrate species. Scores >2.0 indicate conserved positions.
pLI
Probability of Loss-of-function Intolerance. Ranges 0-1. Values > 0.9 indicate the gene is highly intolerant to loss-of-function variants.
PP3
ACMG pathogenic supporting criterion: computational evidence supports a deleterious effect. In Folklore, triggered by BayesDel_noAF or SpliceAI scores.
PVS1
Loss-of-function evidence in a gene where LoF is an established disease mechanism. Folklore applies transcript, expression, mechanism, disease-association, and positional guards before assigning the available strength.
Screening Tier
Priority ranking assigned by the Screening Service. Tier 1 (immediate review), Tier 2 (moderate priority), Tier 3 (low priority), Tier 4 (very low priority).
SIFT
Sorting Intolerant From Tolerant. Predicts amino acid substitution tolerance based on sequence homology. Scores < 0.05 are Deleterious.
SpliceAI
A deep learning model predicting splice site disruption. Produces four delta scores. Threshold >= 0.2 triggers PP3_splice in Folklore.
VCF
Variant Call Format. The standard file format for genomic variant data. Folklore accepts VCF 4.1 and 4.2 files (plain text or bgzipped).
VCEP
Variant Curation Expert Panel. ClinGen panels that define gene-specific ACMG classification thresholds.
VUS
Variant of Uncertain Significance. ACMG classification indicating insufficient evidence to classify as pathogenic or benign. Bayesian points between 0 and 5.
WES
Whole Exome Sequencing. Captures coding regions of the genome. Typically produces 40,000-60,000 variants per sample.
SV/CNV
Constitutional structural and copy-number variants, including supported deletions and duplications, interpreted in Folklore under the Riggs 2020 framework.
MMDWG
ClinGen Mitochondrial Disease Working Group specification used by the dedicated Folklore mtDNA classifier.
WGS
Whole Genome Sequencing. Captures the entire genome. Typically produces 4-5 million small-variant records per sample, depending on the upstream caller and filtering.