Acronyms and Terms

Term	Description
AMP/ACMG/CAP guidelines	Standards and guidelines for annotation, interpretation, and reporting of somatic sequence variants published by the following organizations: •Association for Molecular Pathology (AMP) •American College of Medical Genetics and Genomics (ACMG) •American Society of Clinical Oncology (ASCO) •College of American Pathologists (CAP). Refer to Li et al., J Mol Diagn. 1, 4-23 (2017).
ClinVar	ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/intro) is a public archive of reports of the relationships among human variations and phenotypes, with supporting evidence provided by individual submitters. For more information, refer to the ClinVar section in Disease Association Filters.
Change (Copy Number)	In relation to copy number variants, the field values indicate a reference, deletion, or amplification.
Change (Fold Change)	In relation to copy number variants, fold change is a value derived from the normalized read depth of the gene in the sample relative to the normalized read depth of diploid regions from the same sample.
Copy Number Variants (CNVs)	Refer to the documentation of the secondary analysis pipeline that generated the variant call file (VCF) on the definition and scope. A depth-based caller from DNA sequencing data generates the CNV calls. These calls are defined as regions in the genome with a higher (copy number gain) or lower (copy number loss) number of copies compared to the expected ploidy of the chromosome where they occur.
COSMIC	A database of somatically acquired mutations found in human cancer(https://cancer.sanger.ac.uk/cosmic).
gnomAD	gnomAD consists of the following terms that are defined in this section: •Constraint metrics •LOEUF •misZ •pLi •pNull •pRec •synZ
Constraint Metrics	A set of gene-level metrics (LOEUF, misZ, pLI, pNull, pRec, synZ) that gnomAD provides to help identify genes that are subject to strong selection against various classes of mutations.
LOEUF	The loss of function observed/expected upper bound fraction (LOEUF).
misZ	Z-score indicating gene intolerance of missense variants. Missense Z-score is the corrected missense Z-score.
pLi	The probability of being intolerant of a single loss-of-function variant (like haploinsufficient genes, observed at approximately 0.1 expected).
pNull	The probability of being completely tolerant of loss-of-function variation (observed = expected).
pRec	The probability of being intolerant of two loss-of-function variants (for example, recessive genes observed at approximately 0.5 expected).
synZ	A score indicating gene intolerance to synonymous variants. Synonymous Z-score is the corrected synonymous Z-score.
GE	The Genome Equivalent Sample (GE) is a credit used to run sample analysis when a case is ingested. For more information refer to Usage.
Gel PanelApp	A crowd sourcing tool that allows gene panels to be shared, downloaded, viewed, and evaluated to establish consensus gene panels for each rare disease category. The content includes panels from leading test providers and other genomic resources. For more information, refer to https://panelapp.genomicsengland.co.uk/#!Content.
GIS	Genomic Instability Score (GIS) is a biomarker that can be used as an indicator of homologous recombination deficiency (HRD) status. GIS score can be calculated by measuring relevant genomic scars (for example, loss of heterozygosity (LOH), telomeric-allelic imbalance (TAI), and large-scale state transitions (LST)).
Haploinsufficiency (ClinGen)	A score representing an evidence classification for supporting a relationship between a gene and disease and whether loss (haploinsufficiency) of individual genes or genomic regions is a mechanism for disease (Riggs et al., Clin Genet. 81, 403–412 (2012)). For more information, refer to Filter by Variant Category.
HGVS	The HGVS nomenclature used to describe changes at different levels (for example, with c. prefix for a coding DNA reference sequence, g. for a linear genomic reference sequence, and p. for a protein reference sequence). The Human Genome Organization (HUGO)(https://varnomen.hgvs.org/) authorizes the HGVS nomenclature standard.
HGVSP	The Human Genome Variation Society format describing the protein change relative to the protein reference.
HPO	The Human Phenotype Ontology (HPO) is an ontology of medically relevant phenotypes and disease-phenotype annotations. The resource also provides gene-to-phenotype associations by linking sets of phenotypic features (HPO terms) to diseases caused by mutations in specific genes (https://hpo.jax.org/app/).
HRD	Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to repair DNA double-strand breaks effectively using the homologous recombination repair (HRR) pathway.
IGV	Integrative Genomics Viewer (IGV) is an interactive tool for the visual exploration of genomic data.
Connected Insights	incorporates IGV to allow visualization and inspection of genomic data, including read alignments, at the variant, gene, chromosome, and genome levels.
Low Complexity Region (gnomAD)	A filter to exclude variants inside identified Low-Complexity Genomic Regions (LCR) based on information from gnomAD. In these regions, some categories of variants (for example, structural variants) are more challenging to detect. It can affect the quality of data like allele frequency.
MSI	Microsatellite Instability (MSI) is a change that occurs in certain cells (for example, cancer cells)in which the number of repeated DNA bases in a microsatellite (a short, repeated sequence ofDNA) is different from what it was when the microsatellite was inherited. Microsatellite instability results from the impaired DNA mismatch repair (MMR) and is found most often in colorectal, gastric, and endometrial cancer.
Nirvana	Nirvana, or Illumina Annotation Engine, is a software used by Connected Insights to annotate genomic variants in the uploaded VCF files. For example, Nirvana provides HGVS nomenclature and variant consequences and associates information provided by key sources: functional impact predictors (for example, REVEL, SpliceAI) and databases (for example, ClinVar).
OMIM	OMIM (Online Mendelian Inheritance in Man) is a comprehensive, authoritative compendium of human genes and genetic phenotypes covering all known Mendelian disorders and over 16,000genes (https://www.omim.org/).
Phenopedia	Phenopedia provides a disease-centered view of genetic association studies summarized in the online Human Genome Epidemiology (HuGE) encyclopedia(https://phgkb.cdc.gov/PHGKB/startPagePhenoPedia.action).
PhyloP Score	PhyloP scores measure evolutionary conservation at individual alignment sites. Interpretations of the scores are compared to the evolution that is expected under neutral drift. • Positive scores — Measure conservation (slower evolution than expected) at sites that are predicted to be conserved. • Negative scores — Measure acceleration (faster evolution than expected) at sites that are predicted to be fast-evolving.
PrimateAI	A deep residual neural network for classifying the pathogenicity of missense mutations. PrimateAI is trained on a data set of approximately 380,000 common missense variants. These variants are from humans and six non-human primate species. PrimateAI uses a semi-supervised benign versus unlabeled training regimen. The input to the network is the amino acid sequence flanking the variant of interest and the orthologous sequence alignments in other species without any additional human-engineered features. The output is the pathogenicity score from 0 (less pathogenic) to 1 (more pathogenic).
PrimateAI-3D	A three-dimensional (3D) convolutional neural network trained on 4.5 million common missense variants from 233 primate species. PrimateAI-3D uses 3D convolutions to recognize key structural and evolutionary patterns that may not be apparent from protein sequence alone and learns to infer pathogenicity based on the local enrichment or depletion of common primate variants. PrimateAI-3D does not rely on annotations from clinical variant databases and provides an unbiased review of variant pathogenicity. The output is the pathogenicity score from 0 (less pathogenic) to 1 (more pathogenic).
RxNorm	RxNorm is a normalized naming system for generic and branded drugs and a tool for supporting semantic inter operation between drug terminologies and pharmacy knowledge base systems.The National Library of Medicine (NLM) produces RxNorm.
RNA Fusion Variant	Refer to the documentation of the secondary analysis pipeline that generated the VCF on the definition and scope. RNA fusion variants are generated from RNA sequencing data and include interchromosomal or intrachromosomal translocation resulting in the fusion typically within two genes.
RNA Splice Variant	Refer to the documentation of the secondary analysis pipeline that generated the VCF on the definition and scope. RNA splice variants are generated from RNA sequencing data. These variants indicate a splicing event that deviates from the expected transcripts of a gene typically resulting in an exon loss.
Small Variants	Refer to the documentation of the secondary analysis pipeline that generated the VCF on the definition and scope. Typically, the short read caller from DNA sequencing data generates small variant calls. These small variant calls include single nucleotide variants (SNVs), multiple nucleotide variants (MNVs), and deletions and insertions (indels/delins) that are typically less than or equal to 50 bp in length. Connected Insights assigns a small variant category to deletions and insertion calls represented by a full sequence change of reference allele and alternate allele in the VCF as compared to structural variants.
Somatic Variant	An alteration in DNA that occurs after conception and is not present within the germline.Somatic variants can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children.
SpliceAI	The delta score of a variant defined as the maximum of the following ranges from 0 to 1: • Acceptor gain • Acceptor loss • Donor gain • Donor loss The score can be interpreted as the probability of the variant being splice-altering. In the paper,a detailed characterization is provided for 0.2 (high recall), 0.5 (recommended), and 0.8 (high precision) cutoffs. Delta position provides information about the location where splicing changes relative to the variant position. Positive values are downstream of the variant, while negative values are upstream.
Structural Variants (SVs)	Refer to the documentation of the secondary analysis pipeline that generated the VCF on the definition and scope. Typically, structural variants VCFs are generated by a breakend caller from DNA sequencing data and include deletions and insertions ≥ 50 bp in length, duplications < 10kb, and translocations. DNA gene-fusions can be a result from a large deletion or translocation.Connected Insights assigns a structural variant category to large deletions and insertions calls represented with a symbolic alternate allele in the VCF (, , or ) as compared to small variants.
TMB	Tumor Mutational Burden– a measurement of the number of non-synonymous somatic mutations (single nucleotide variants and small insertions/deletions) per megabase in coding regions.
Triplosensitivity (ClinGen)	A score representing an evidence classification for supporting a relationship between a gene and disease and whether gain (triplosensitivity) of individual genes or genomic regions is a mechanism for disease (Riggs et al., Clin Genet. 81, 403–412 (2012)). For more information, refer to Functional Impact Filters.
VAF	Variant Allele Frequency (VAF) is the proportion of reads supporting the variant call.
VCF	Variant Call File (VCF) is a text file format containing meta-information lines and a header line followed by data lines. These lines contain information about a position in the genome.