Terms used throughout this pipeline’s documentation, explained for people who are not bioinformaticians.
Allele — One of the possible versions of a gene or variant at a specific position. You have two alleles at most positions (one from each parent). Example: at a SNP position, the reference allele might be A and the alternate allele G.
Allele Frequency (AF) — How common a variant is in a population. AF=0.01 means 1% of people carry it. Common in gnomAD and ClinVar annotations.
ALT — The alternate allele; the version that differs from the reference genome. In a VCF file, REF=A, ALT=G means the reference has A but this sample has G.
Autosomal Dominant — A variant in one copy of a gene is enough to cause the condition. Contrast with autosomal recessive.
Autosomal Recessive — Both copies of a gene must be affected (homozygous or compound heterozygous) for the condition to manifest. Having one copy makes you a carrier.
BAM — Binary Alignment Map. A binary file containing sequencing reads aligned to a reference genome. Typically 80-120 GB for 30X WGS. Requires a .bai index file.
Benign — A variant classification meaning the variant is not disease-causing. The opposite of pathogenic.
BND — Breakend. A structural variant type where read pairs map to unexpected locations (different chromosomes or distant positions). Most are artifacts.
Carrier — A person who has one copy of a recessive disease variant (heterozygous). Carriers are typically unaffected but can pass the variant to children.
chrM — Chromosome M (mitochondrial). The small circular genome inside mitochondria (~16,569 bp). Inherited maternally.
ClinVar — NCBI’s public database of clinically significant genetic variants. Each entry includes a significance classification (pathogenic, benign, VUS, etc.) and supporting evidence.
CNV — Copy Number Variant. A region of the genome that is deleted or duplicated relative to the reference. Detected by CNVnator (depth-based) and Manta/Delly (read-pair based).
Compound Heterozygous — Having two different pathogenic variants in the same gene, one from each parent. Can cause autosomal recessive disease even though neither variant is homozygous.
Coverage / Depth — The average number of sequencing reads covering each position. “30X” means each position is read ~30 times on average. Higher coverage = more accurate variant calling.
CRAM — Compressed Reference Alignment Map. A compressed version of BAM (40-60% smaller) that stores reads as differences from the reference genome.
De Novo — A variant that appeared for the first time in an individual (not inherited from either parent). Typically 50-100 de novo SNVs per genome.
DEL — Deletion. A structural variant where a segment of DNA is missing compared to the reference.
DeepVariant — Google’s deep learning-based variant caller. Uses a neural network trained on labeled sequencing data to call SNPs and indels.
DUP — Duplication. A structural variant where a segment of DNA is copied one or more extra times.
FASTQ — A text-based format for storing raw sequencing reads and their quality scores. Paired-end sequencing produces two files (R1 and R2).
gnomAD — Genome Aggregation Database. Contains allele frequencies from ~140,000 exomes and ~76,000 genomes. The standard reference for how common a variant is in healthy populations.
GRCh37 / hg19 — The older human genome reference assembly (2009). Some vendors still deliver data aligned to this build.
GRCh38 / hg38 — The current human genome reference assembly (2013, with updates). This pipeline uses GRCh38 exclusively.
Haplogroup — A group of similar genetic variants inherited together, used to trace ancestry through maternal (mitochondrial) or paternal (Y-chromosome) lineages.
Heteroplasmy — Having a mixture of different mitochondrial DNA sequences within the same cell. Low-level heteroplasmy (<5%) is normal and increases with age.
Heterozygous (het, 0/1) — Having two different alleles at a position (one reference, one alternate). Written as 0/1 in VCF genotype fields.
HLA — Human Leukocyte Antigen. A highly polymorphic gene complex on chromosome 6 involved in immune function. Difficult to type accurately from short-read WGS.
Homozygous (hom, 1/1) — Having two copies of the same alternate allele at a position. Written as 1/1 in VCF genotype fields.
Imputation — Statistical prediction of missing genotypes based on known patterns of genetic variation (linkage disequilibrium). Used to fill gaps in genotyping array data.
Indel — An insertion or deletion of one or more bases. Distinct from structural variants (which are larger, typically >50 bp).
INV — Inversion. A structural variant where a segment of DNA is flipped in orientation relative to the reference.
Likely Pathogenic — A variant classification one step below “Pathogenic.” Strong evidence of disease association but not yet definitive.
Loss of Function (LoF) — A variant that is predicted to destroy the function of a gene (stop-gain, frameshift, splice donor/acceptor disruption). Also called “HIGH impact” by VEP.
MAF — Minor Allele Frequency. The frequency of the less common allele at a variant position. Often used interchangeably with AF for rare variants.
Manta — An SV caller that uses paired-end read distance and split reads to detect structural variants. Fast and accurate for deletions and duplications.
Missense — A single nucleotide change that results in a different amino acid in the protein. May or may not affect protein function.
PASS — A VCF filter status indicating the variant passed all quality filters. Non-PASS variants have quality concerns and should generally be excluded from analysis.
Pathogenic — A variant classification meaning the variant is known to cause disease. The strongest clinical significance level in ClinVar.
Penetrance — The proportion of people with a pathogenic variant who actually develop the associated disease. “Incomplete penetrance” means not everyone with the variant gets sick.
PGx / Pharmacogenomics — The study of how genetic variants affect drug metabolism and response. Used to guide medication selection and dosing.
PolyPhen — A tool that predicts whether an amino acid change is damaging to protein function. Scores range from 0 (benign) to 1 (probably damaging).
REF — The reference allele; the version found in the reference genome at that position.
ROH — Run of Homozygosity. A long stretch of DNA where both copies are identical. Large ROH segments can indicate parental relatedness.
SIFT — A tool that predicts whether an amino acid change affects protein function. Scores < 0.05 are predicted “deleterious”; > 0.05 are “tolerated.”
SNP / SNV — Single Nucleotide Polymorphism / Variant. A single base-pair change (e.g., A>G). The most common type of genetic variant (~4-5 million per genome).
Star Allele — A standardized naming system for pharmacogene variants (e.g., CYP2C19*2, CYP2D6*4). Used by PharmCAT and pharmacogenomics databases.
STR — Short Tandem Repeat. A DNA sequence of 2-6 bases repeated many times in a row (e.g., CAGCAGCAG…). Pathogenic expansions cause diseases like Huntington’s.
SV — Structural Variant. A large-scale genomic rearrangement (>50 bp): deletion, duplication, inversion, insertion, or translocation.
Tabix / TBI — An index format for coordinate-sorted, block-compressed files (VCF, BED). Allows rapid random access to specific genomic regions. The .tbi file must accompany .vcf.gz files.
VCF — Variant Call Format. A tab-delimited text file listing genetic variants with their position, alleles, quality scores, and annotations. The standard format for variant data.
VEP — Variant Effect Predictor. Ensembl’s tool for annotating variants with functional consequences, population frequencies, and pathogenicity predictions.
VUS — Variant of Uncertain Significance. Not enough evidence to classify as pathogenic or benign. Not clinically actionable. May be reclassified in the future as more data accumulates.
WGS — Whole Genome Sequencing. Sequencing the entire ~3.1 billion base pairs of a genome. Produces FASTQ files that are processed through this pipeline.
X-linked — A gene located on the X chromosome. Males (XY) have only one copy, so a single pathogenic variant can cause disease. Females (XX) have two copies and may be carriers.