Term/abbreviation

Description

ACMG

American College of Medical Genetics and Genomics

Actionability

A measure of whether a piece of genetic information known to the clinician is clinically meaningful and worth acting on with the patient

Actionable Gene

A gene responsible for a given disease that has direct or indirect therapeutic applications

Alignment

The process of arranging sequencing reads against a reference genome to identify similarities and differences

Allele

One of two or more alternative forms of a gene or genetic sequence at the same locus on a chromosome

AMP

Association for Molecular Pathology

API

Application Programming Interface: set of definitions and protocols for building and integrating application software

ASCO

American Society of Clinical Oncology

Assay

A set of predefined configurations and protocols used in laboratory analysis, specifically designed to focus on and prioritize specific areas of interest

B

Benign - one of the possible classes of a genetic variant according to its likelihood of being pathogenic; see the term “Variant Classification”

BAM

Binary Alignment Map

BWA

Burrows-Wheeler Alignment algorithm - industry standard open-source aligner

Carrier Screening

Genetic testing to determine if a person carries a gene mutation that could be passed to offspring

CDS

Clinical Decision Support - health information technology that provides clinicians with knowledge and person-specific information to enhance health and health care

ClinGen

Clinical Genome Resource

CMA

Chromosomal Microarray Analysis

CNA

Copy Number Aberration

CNV

Copy Number Variation - genomic alterations where sections of DNA are duplicated or deleted

Coverage

The average number of times a given base in the genome is sequenced; also referred to as sequencing depth

Curated Data

Genetic data that has been reviewed, organized, standardized, and annotated by experts to ensure accuracy, consistency, and clinical relevance prior to use in interpretation

DNA

Deoxyribonucleic Acid - the molecule that carries the genetic information used in the growth, development, functioning, and reproduction of all living organisms

ECS

Expanded Carrier Screening

ESHG

European Society of Human Genetics

FASTQ

A text-based format for storing both biological sequences and their quality scores

FreeBayes

Open-source variant calling tool

GA4GH

Global Alliance for Genomics and Health

GATK

Genome Analysis Toolkit - industry-standard variant calling software

GenCC

Gene Curation Coalition

Genetic Profile

A collection of characterized genetic variants and markers of an individual derived from genomic analysis, used to support clinical interpretation

Genotype

The complete set of genetic information of an organism, or the genetic constitution at a specific locus, typically described in terms of alleles present

Germline Variant

A genetic variant inherited from a parent that is present in all cells

GIAB

Genome in a Bottle

GRCh37

Genome Reference Consortium Human Build 37

GRCh38

Genome Reference Consortium Human Build 38

Haplotype

A group of genes within an organism that was inherited from a single parent

HGMD

Human Gene Mutation Database

HGVS

Human Genome Variation Society - a standardized nomenclature system for describing gene variations

HPO

Human Phenotype Ontology

HRD

Homologous Recombination Deficiency - the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair pathway

Indel

Insertion or deletion of nucleotides in the genome

ISCN

International System for Human Cytogenomic Nomenclature

Knowledge Base

A centralized, structured repository of curated genetic information, panels, classified variants, and references used to support variant interpretation and clinical decision making within Franklin

LP

Likely Pathogenic - one of the possible classes of a genetic variant according to its likelihood of being pathogenic; see the term “Variant Classification”.

MAF

Minor Allele Frequency - the frequency at which the second-most-common allele occurs in a given population

MANE

Matched Annotation from NCBI and EBI

MMR

Mismatch Repair - system within cells that corrects errors that spontaneously occur during DNA replication

MNV

Multi-Nucleotide Variant

MOI

Mode of Inheritance - the manner in which a genetic trait or disease is passed from one generation to another

MSI

Microsatellite Instability - a measure of predisposition to mutation that results from impaired DNA Mismatch Repair

NGS

Next-Generation Sequencing - a general term used to describe high throughput sequencing technologies

NIST

National Institute of Standards and Technology

NMD

Nonsense-Mediated Decay - a cellular mechanism that degrades mRNA transcripts containing premature stop codons

P

Pathogenic - one of the possible classes of a genetic variant according to its likelihood of being pathogenic; see the term “Variant Classification”

P/M/DN

Parental / Maternal / De novo – Inheritance indication of a variant. The variant might be inherited paternally or maternally; In cases where the variant is a novel mutation, not inherited paternally or maternally, it is indicated as De Novo

Panel Sequencing

Targeted sequencing of specific sets of genes relevant to conditions

Pathogenicity

The potential capacity of genetic variants to cause disease

Phenotype

The observable characteristics or traits of an organism resulting from the interaction of its genotype with the environment

Pipeline

A sequence of automated computational processes applied to sequencing data (e.g., alignment, variant calling, annotation, filtration) to transform raw reads into interpretable results

PM (PM1, PM2, PM3, PM4, PM5, PM6)

Pathogenic Moderate indication - indication category of moderate pathogenicity according to ACMG/AMP guidelines. Includes the criteria PM1, PM2, PM3, PM4, PM5, PM6

PP (PP1, PP2, PP3, PP4, PP5)

Pathogenic Supporting indication - indication category of supporting pathogenicity according to ACMG/AMP guidelines. Includes the criteria PP1, PP2, PP3, PP4, PP5

PS (PS1, PS2, PS3, PS4)

Pathogenic Strong indication - indication category of strong pathogenicity according to ACMG/AMP guidelines. Includes the criteria PS1, PS2, PS3, PS4

Pseudonymization

Data processing technique in which personally identifiable information is replaced with one or more artificial identifiers so that the data can no longer be attributed to a specific individual without additional information kept separately

QC

Quality Control - the processes and metrics used to assess the reliability and integrity of sequencing and analysis data (e.g., read depth, mapping quality, variant confidence scores)

Reference Genome

A representative digital nucleic acid sequence assembled as a standard against which sequencing reads are aligned and compared (e.g., GRCh37, GRCh38)

RNA

Ribonucleic Acid - a nucleic acid that plays a central role in the coding, decoding, regulation, and expression of genes

SAM

Sequence Alignment Map

SNP

Single Nucleotide Polymorphism

SNP Calling

Process to determine positions where polymorphisms exist compared to a reference sequence

SNV

Single Nucleotide Variant

Somatic Variant

A genetic variant acquired during a person's lifetime, not inherited; can occur in any cell except germ cells and is not passed to children

SV

Structural Variants - large genomic alterations typically encompassing at least 50 bp

TMB

Tumor Mutational Burden - a genetic characteristic measuring the number of non-inherited mutations per million bases of investigated genomic sequence

UPD

Uniparental Disomy - genetic abnormality where both copies of a chromosome are inherited from one parent

VAF

Variant Allele Frequency

Variant Classification

The categorization of a genetic variant according to its likelihood of being pathogenic (e.g., Benign, Likely Benign, VUS, Likely Pathogenic, Pathogenic) based on established criteria such as ACMG/AMP

VCF

Variant Call Format - output file format used to store genetic sequence variations

VICC

Variant Interpretation for Cancer Consortium

VUS

Variant of Uncertain Significance

WES

Whole Exome Sequencing - sequencing focusing on coding regions of the genome

WGS

Whole Genome Sequencing - comprehensive analysis of the entire genome

Term/abbreviation

Definition

Active User

A unique Franklin user account that has logged in and performed at least one analytical action within a defined monitoring period, as used in platform utilization and post-market surveillance metrics

Analytical Version

Version identifier that changes when Franklin changes its secondary analysis (alignment, variant calling). New versions require analytical performance validation

Benchmark

Pre-defined performance thresholds used to evaluate the quality and accuracy of analysis results

Case

A patient sample analysis instance in Franklin, containing genetic data and associated metadata

Clinical Version

Version identifier that changes when Franklin changes its tertiary analysis (classification, priority, benchmark thresholds). New versions require clinical performance validation

DB

Database

Hard Panel

Hard panels are applied before the annotation phase, and once implemented, they restrict the scope of analysis, preventing any expansion. This panel type is primarily used for regulatory compliance, ensuring that only the variants within the panel are reported and avoiding secondary findings. Hard panels require all variants found on the panel to be reported and are useful for fixed regulatory requirements, trimming the analysis before annotation for strict adherence to compliance standards

Lab Integration

The interface between Franklin and laboratory workflows, ranging from manual uploads to API integration to full laboratory information system integration

Non-Standard Case

A case using a custom template workflow, typically accessed via sample bulk upload

NR

Not Relevant - the marking of a variant as irrelevant for analysis, can be set using the “NR” button

Primary Analysis

Initial processing of raw sequencing data by the sequencer

Secondary Analysis

Alignment of sequencing reads to reference genome and variant calling

Soft Panel

A soft panel is dynamic and acts as a filter to restrict the view of variants. It can be applied after the case has been generated, allowing for flexibility in addressing specific variants of interest. Additional soft panels can be added to refine the analysis further. Soft panels mask genes and offer the option to decide which variants to report, as seen in cases where broad tumor profiles, like TSO500, are used with soft panels applied post-analysis to maintain existing ordering procedures while expanding the scope of the analysis

Solution

The Solution in Franklin refers to the complete, end-to-end genetic analysis and interpretation process. The solution covers everything from raw data to an entirely generated report. It includes all necessary components, such as workflows, panels, assays, and associated configurations, and encompasses both secondary and tertiary analysis. Each solution is designed to address specific clinical diagnostic or research needs, providing a seamless and integrated experience. Solutions are tailored to categories like germline or oncology, ensuring users have a comprehensive set of tools aligned with their clinical or research objectives

Solution Category

Highest-level categorization of genetic analysis in Franklin (e.g., Oncology, Reproductive Health, Genetics)

Standard Case

Pre-defined case type available through the "New Case" user flow, accessible to all users

Template Workflow

A pre-configured set of parameters (pipeline, kit, sequencer, file inputs, QC metrics) tailored for specific genetic tests

Tertiary Analysis

Annotation, filtering, and interpretation of variants

Validated Workflow

Validated Workflow in Franklin refers to the combination of a specific kit and a corresponding workflow that has been verified for accuracy and performance. Examples of validated workflows include TSO500 by Illumina, Agilent CGP, Thermo Fisher OCA, and Oncomine Comprehensive. Franklin offers support for more than 500 validated workflows, each of which resides within an Assay. These workflows are essential for ensuring that each analysis is conducted according to the specifications of the kit used, making it possible to consistently deliver high-quality, reliable results

Workbench

The Workbench is the primary interface for case analysis, providing essential information needed to evaluate a sample. Once processing is complete, the evaluation begins from this page. When the "WB" (abbreviation for Workbench) icon appears within the variant list, it means that the variant is included in the workbench

Workflow

A pre-configured set of parameters including pipeline, kit, sequencer, file inputs, and quality control metrics

Source

Description

ClinGen

Clinical Genome Resource - NIH-funded resource dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants

ClinVar

Public archive of reports on relationships between human genetic variants and phenotypes, maintained by NCBI

COSMIC

Catalogue of Somatic Mutations in Cancer - database of somatic mutations found in human cancers

dbSNP

Database of Single Nucleotide Polymorphisms - NCBI database of genetic variation

gnomAD

Genome Aggregation Database - database aggregating and harmonizing exome and genome sequencing data from large-scale sequencing projects

OMIM

Online Mendelian Inheritance in Man - comprehensive compendium of human genes and genetic phenotypes

RefSeq

Reference Sequence Database - NCBI collection of curated, non-redundant genomic DNA, transcript, and protein sequences

1000 Genomes

Population-level genomic reference dataset providing allele frequencies across diverse human populations

APOGEE

Machine-learning meta-predictor used for pathogenicity prediction of mitochondrial variants

BayesDel

Deleteriousness meta-score used to predict the pathogenicity of missense and splice-site variants

BRCA Exchange

Public resource aggregating BRCA1 and BRCA2 variant data and expert classifications from ENIGMA and other consortia

DANN

Deep-learning based pathogenicity score for variants across the genome

dbscSNV

Database of splice-consensus single nucleotide variants used for splice-site variant prediction

dbVAR

NCBI database of human genomic structural variation

DECIPHER

Database of submicroscopic chromosomal imbalances and phenotypes, used for clinical interpretation of CNVs

DGV

Database of Genomic Variants - catalogue of structural variation in the human genome

ESP 6500

NHLBI Exome Sequencing Project dataset providing allele frequencies from ~6,500 exomes

ExAC

Exome Aggregation Consortium - aggregation of exome sequencing data providing allele frequencies (predecessor of gnomAD)

FATHMM

Functional Analysis through Hidden Markov Models - tool predicting the functional consequences of coding and non-coding variants

FDA Approved Drugs

Public list of drugs approved by the U.S. Food and Drug Administration used for therapeutic annotation

fitCons

Score estimating the probability that a genomic position is under natural selection (fitness consequences)

Gene2Phenotype

Curated dataset of gene-disease associations maintained by EBI, used to support clinical interpretation

GenoCanyon

Functional potential score predicting the significance of non-coding variants

GERP

Genomic Evolutionary Rate Profiling - conservation score indicating evolutionary constraint at a given genomic position

MetaLR

Logistic-regression meta-predictor of missense variant deleteriousness

MetaSVM

Support-vector-machine meta-predictor of missense variant deleteriousness

MitoMap

Compendium of polymorphisms and mutations of the human mitochondrial DNA

MitoTip

Prediction score for the pathogenicity of mitochondrial tRNA variants

Monarch

Monarch Initiative - integrated platform linking genes, phenotypes and diseases across species

MutationAssessor

Tool predicting the functional impact of amino acid substitutions based on evolutionary conservation

MutationTaster

Prediction tool evaluating the disease-causing potential of DNA sequence alterations

Orphanet

European portal for information on rare diseases and orphan drugs

PharmGKB

Pharmacogenomics Knowledgebase - curated resource on the impact of genetic variation on drug response

PolyPhen-2

Polymorphism Phenotyping v2 - tool predicting the possible impact of amino acid substitutions on the structure and function of a human protein

PrimateAI

Deep-learning based pathogenicity prediction for missense variants, trained on non-human primate variation

PubMed

NIH-maintained database of biomedical literature references and abstracts

REVEL

Rare Exome Variant Ensemble Learner - ensemble meta-predictor for missense variant pathogenicity

SIFT

Sorting Intolerant From Tolerant - tool predicting whether an amino acid substitution affects protein function

SpliceAI

Deep-learning tool predicting splice-altering effects of genetic variants

TopMed BRAVO

Trans-Omics for Precision Medicine BRAVO - allele frequency dataset derived from the TOPMed program

TrAP

Transcript-inferred Pathogenicity score - prediction score for the impact of variants on splicing and protein function

UK10K

UK10K Project - dataset providing allele frequencies from ~10,000 UK-based individuals

UniProt

Universal Protein Resource - comprehensive, high-quality database of protein sequence and functional information

VARITY

Meta-predictor of missense variant pathogenicity based on machine learning