ACMG
American College of Medical Genetics and Genomics. Publisher of the 2015 variant classification guidelines used by Helix Insight.
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 Helix Insight but does not contribute to ACMG classification.
BayesDel_noAF
The ClinGen SVI-calibrated computational meta-predictor used by Helix Insight for PP3 and BP4 ACMG criteria. The "_noAF" suffix indicates allele frequency is excluded from its model.
Benign
ACMG classification indicating the variant is not disease-causing. Requires strong benign evidence (Bayesian points <= -7).
BP4
ACMG benign supporting criterion: computational evidence suggests no impact on gene or gene product. In Helix Insight, triggered by BayesDel_noAF score <= -0.180.
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. Helix Insight uses ClinVar for PS1, PP5, BP6 criteria and classification override.
Compound Heterozygote
An individual carrying two different pathogenic variants in the same gene, one on each chromosome. Relevant for autosomal recessive conditions.
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 Helix Insight 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 Helix Insight.
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 indicating the variant is probably not disease-causing. Bayesian points between -1 and -6.
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 indicating the variant is disease-causing. Requires Bayesian points >= 10 or BA1 stand-alone benign override.
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 Helix Insight, triggered by BayesDel_noAF or SpliceAI scores.
PVS1
ACMG very strong pathogenic criterion: null variant in a gene where loss-of-function is a known mechanism. Requires pLI > 0.9 or LOEUF < 0.35.
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 Helix Insight.
VCF
Variant Call Format. The standard file format for genomic variant data. Helix Insight 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.
WGS
Whole Genome Sequencing. Captures the entire genome. Typically produces 4-5 million variants per sample.