ACMG – The American College of Medical Genetics and Genomics

Adequately sequenced – A base in the genome that has sufficient data (8 “reads” or more) to detect a genetic variant. 

Alternate variant – A genetic variant that differs from the sequence in the reference genome. Sometimes also referred to as the heterozygous alternate variant.

AMP – Association for Molecular Pathology

Annotation – The process of associating available clinical and scientific information with a genetic variant.

Barcode (or ‘Test code’) – A code uniquely identifying a patient’s genetic sample. It is placed on the collection tube(s) and every page of test requisition forms and patient consents.

“bp” – “base pair”. One base in a DNA strand (A, G, C, or T).

Calculated severity score – A weighted score from a number of computational prediction tools and variant databases classifying the variant’s conservation and effect on protein.

CAP accreditation – College of American Pathologists (CAP) Laboratory Accreditation helps laboratories: Maintain accuracy of test results and ensure accurate patient diagnosis. Meet required standards from CLIA, FDA and OSHA. CAP requirements commonly exceed the standards, bolstering patient care and safety.

CLIA certification – The Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory testing and require clinical laboratories to be certified by the Center for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing.

ClinVar – A user-submitted, crowd based resource reporting relationships among medically important variants and symptoms.

Conservation – Degree of consistency of genomic loci across different species and populations.

Curation – The process of review and qualification of gene, variant and disease associated evidence from medical publications into a database

Diagnostic console notations

  • [ClinGen] An NIH-funded database that includes disease causing genes and variants.
  • [ClinVar] Disease association is based on ClinVar database
  • [dbSNP] A database of single nucleotide polymorphisms found in populations
  • [DGV] Disease association is based on Database of Genetic Variants; a database tracking copy number variants
  • [Gene] Disease association of the variant that has not been previously reported in peer reviewed clinical literature, however other variants in this gene were reported to be associated with disease(s).
  • [HGMD] Disease association is based on HGMD Professional database
  • [MITOMAP] A database tracking variants in the mitochondrial genome
  • [OMIM] Disease association is based on Online Mendelian Inheritance in Man database
  • [ORPHANET] Disease association is based on rare disease knowledge base Orphanet
  • [Protein] No clinically relevant variants in this gene have been previously reported in peer reviewed clinical literature, however protein level alterations in the product of this gene were reported to be associated with disease(s)
  • [PROTEOME] Disease association is based on PROTEOME database
  • [REGULATORY] The variant is overlapping known regulatory element, such as Transcription Factor binding site, miRNA site or enhancer
  • [VARIANT] In peer reviewed clinical literature this variant has been reported to be associated with disease(s)

D.O.B. – Date of birth; handwritten dates must show month in three letters (e.g. May, Dec)

Epigenetic modification –  A genetic change that does not change the DNA, but can change how active or inactive a gene is.

Fusion – A genetic change causing two genes to become fused and yield a new gene product

Gene expression – Gene expression is the process by which the information encoded in a gene is used to either make RNA molecules that code for proteins or to make non-coding RNA molecules that serve other functions. 

Genetic sex (male / female) – A parameter required for adequate detection and interpretation of genetic variants on the chromosomes X/Y.

Germline variant – Genetic variants present in all body cells that originate in reproductive cells, either de novo or inherited from the parents.

Genomic Intelligence – The proprietary analysis software developed and used by Variantyx to analyze genetic data.

Haploinsufficiency – A situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally. Another way to define haploinsufficiency is as a condition that arises when the normal phenotype requires the protein product of both alleles, and reduction of 50% of gene function results in an abnormal phenotype.

Heterozygous – One allele of the tested individual conforms to the reference DNA (wild type / reference genome), and one allele conforms to a different sequence than the wild type / reference genome.

HGMD – Human Gene Mutation Database; a manually curated mutation database.

Homozygous alternate – Both alleles of the tested individual conform to a different sequence than the wild type / reference genome.

Homozygous reference – Both alleles of the tested individual conform to the wild type / reference genome

HPO – Human Phenotype Ontology; standardized way of describing symptoms of human disease.

Incidental findings – Clinically relevant variants that are discovered unintentionally and are unrelated to the current medical condition of the patient.

In Silico gene panel – Lists of genes for which variants are shown during analysis:

  • ACMG panels were produced based on the ACMG guidelines
  • Cancer panel were developed by PhD-level Variantyx scientists based on oncology publications and germline COSMIC entries
  • Carrier Risk filter – A list of variants for which there is evidence of passing on the disease to an offspring
  • Secondary Findings filter – Variants with evidence for increased disease risk that are not related to a person’s symptoms.

Interpretation categories – The definition of a genetic variant in relation to a human disorder.

  • Pathogenic – A genetic variant that causes a disorder or an increased risk of a disorder
  • Likely pathogenic – A genetic variant that is highly likely to cause or increase the risk of a genetic disorder.
  • Uncertain – A genetic variant that may or may not cause or increase the risk of a genetic disorder. This classification may result from either insufficient evidence or conflicting evidence.
  • Likely benign – A genetic variant that is highly unlikely to cause or increase the risk of a genetic disorder.
  • Benign – A genetic variant that is not expected to cause or increase the risk of a genetic disorder.

MOI  – Mode of inheritance (of a condition or a disease).

Nonsynonymous SNV – A single nucleotide variation that alters the amino acid sequence of a protein.

PCR – Polymerase chain reaction; a process used in some forms of genetic testing.

Phenotype – A trait or feature of a person.

Pop. Freq. (or PAF)  – Population allele frequency; the incidence or abundance of the genetic variant in the population (1 stands for 100%).

Population frequencies (1000 Genomes Project, ExAC, gnomAD, NHLBI Exome, genBank Sequencing Project) – Describes incidence of specific variants within healthy population cohorts. See respective organization websites for descriptions.

Prediction – A computational algorithm that determines the severity of a variant based on its biological effect downstream from the DNA (in the protein)

Primary finding(s) – A list of variants deemed to be potentially related to the patient phenotype.

Proband – The subject of the genetic test.

Pseudogene – A gene that is highly similar to a functional gene, but is often non-functional.

Read depth (X) – The number of times a given coordinate location is sequenced during whole genome sequencing (e.g. 8x, 25x, 30x, etc.)

Reanalysis – Reviewing pre-existing genetic data to determine if a variant is present in a gene with a new gene-disease relationship.

Reclassification – Updating the classification of a genetic variant, often based on new research or evidence (e.g. from uncertain to likely pathogenic).

Reference – The human DNA sequence that is considered as the basis, correct, “wild-type” sequence. Variantyx uses “hg38” developed by the human genome sequencing project.

RVIS (Residual Variation Intolerance Score) – Designed to rank genes in terms of whether they have more or less common functional genetic variation relative to the genome wide expectation given the amount of apparently neutral variation the gene has. A gene with high score has more common functional variation, and a gene with low score has less and is referred to as “intolerant”

Sanger (sequencing) validation – Used as an orthogonal sequencing method for verification or validation of a variant detected in whole exome or whole genome NGS sequencing.

Secondary findings – Variants are associated with increased disease risk of a condition that is not the primary reason for testing.

SIFT, MutationAssessor, Mutation Taster, GWAVA, PolyPhen2, FATHMM, Silva, LRT – Severity prediction tools, see respective organization website

SiPhy, GERP++, PhyloP, PhastCons – Conservation prediction tools, see respective organization website

Southern blot – A gold-standard genetic test for confirming certain genetic variants.

Specimen type – Tissue, blood, or extracted DNA. We track the type as it might affect the sequencing results in some cases. This detail is important for documentation and QC reasons

Triplosensitivity – A mechanism of genetic disorders when the disorder is caused by a gain of one gene leading to an increase in the gene product (the protein).

Uniparental disomy – An instance where a person has both copies of a single chromosome from one parent instead of one chromosome from each parent (e.g. both copies of chromosome 1 are from the mother and no copies of chromosome 1 are from the father).

Untranslated Regions (5’ and 3’) – Regions of the DNA that do not get translated into mRNA.

Variant – A change in DNA that has many different types:

  • Deletion/insertion – A small loss or gain of DNA.
  • Intronic – A variant that occurs in the intron.
  • Exonic – A variant that occurs in the exon.
  • Intergenic – A variant that occurs in the DNA between genes.
  • Copy number variants (duplications/deletions) – Large gains or losses of DNA.
  • Regions of homozygosity – A region where DNA is identical on the two chromosome copies.
  • Mobile element insertions – An insertion of a class of DNA that can move and replicate. 
  • Inversions – A rearrangement in the order of DNA on a chromosome.
  • Aneuploidy – A gain or loss of one or more whole chromosomes.
  • Mitochondrial – A genetic change that occurs in the mitochondrial genome.
  • Structural – A larger loss or gain of DNA that affects the structure of the gene or chromosome.
  • Heteroplasmy – A genetic change in the mitochondrial genome that is present in only a subset of mitochondria.
  • Homoplasmy – A genetic change in the mitochondrial genome that is present in all mitochondria.
  • Short tandem repeat expansion – An expansion of a portion of unstable, repetitive DNA.

X Inactivation – A natural process whereby one copy of the X chromosome is inactivated in a cell.