genomics database and variant reference cohort · BEGINNER LESSON
ExAC
ExAC, the Exome Aggregation Consortium, is a large database of protein-coding genetic variants collected from more than 60,000 mostly unrelated human exomes. It is used as a reference set for studying how common variants are and for helping judge whether a variant is too frequent to fit a disease claim. [0,1,2]
What ExAC is and what it measures
ExAC is a collection of whole-exome sequencing data from 60,706 unrelated people, assembled from multiple projects and reprocessed together. An exome is the protein-coding part of the genome, so ExAC measures variation in protein-coding DNA and the population frequency of those variants. The database was designed as a public resource and includes a large catalogue of human protein-coding variation. [0,1,2]
[1] [PDF] Using large-scale genomic data sets to understand the impact of ... [2] Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification - Genetics in Medicine [3] News & views
How the data were built
The samples were selected to be high quality, unrelated, and generally not known to have severe pediatric disease, although such cases were depleted rather than completely absent. All data were reprocessed with a common pipeline and jointly called across samples, which means variant calls were made in a consistent way across the whole set. This harmonized analysis helped make the resource useful across many studies. [0,2]
[1] [PDF] Using large-scale genomic data sets to understand the impact of ... [3] News & views
What scientists use ExAC for
One use is filtering: if a variant is too common in ExAC, it is unlikely to explain a rare disease. Another use is checking penetrance, meaning how often a variant that is thought to be disease-causing actually shows disease in people who carry it. ExAC is also used to look for genes or regions that have fewer loss-of-function variants than expected. Loss-of-function means a change predicted to prevent normal protein function. [0,1,2]
[1] [PDF] Using large-scale genomic data sets to understand the impact of ... [2] Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification - Genetics in Medicine [3] News & views
Important limits
ExAC is not a perfect snapshot of healthy people. Many samples came from disease-specific or population studies, so phenotype data were limited and most people were not available for recontact. The sample set also includes people from diverse populations, which is useful for filtering but can complicate interpretation if ancestry is not considered. Some publications also note problems such as nonstandard variant naming and challenges from pseudogenes, which are similar DNA sequences that can make analysis harder. [0,1]
[1] [PDF] Using large-scale genomic data sets to understand the impact of ... [2] Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification - Genetics in Medicine
SEE THE IDEA
How ExAC is used
Exomes from many unrelated people are gathered from several studies.
All data are reprocessed with one pipeline and variants are called together.
Researchers check how common a variant is across populations.
Observed loss-of-function variants are compared with expected numbers.
Samples are collected and standardized first, then used to measure variant frequency and to test whether genes show less variation than expected.
ExAC turns many exomes into a shared reference for frequency filtering and for spotting unusually constrained genes.
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Sources and further reading
This general lesson was generated from public source material. It explains a concept; it does not interpret a private paper or provide medical advice.