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majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.<h4>Methods</h4>We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.<h4>Results</h4>We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of\u00a0these variants.<h4>Conclusions</h4>These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.","bibjson":{"author":[{"initials":"L","lastname":"Hensen","name":"Hensen L"},{"initials":"PT","lastname":"Illing","name":"Illing PT"},{"initials":"E","lastname":"Bridie Clemens","name":"Bridie Clemens E"},{"initials":"THO","lastname":"Nguyen","name":"Nguyen THO"},{"initials":"M","lastname":"Koutsakos","name":"Koutsakos M"},{"initials":"CE","lastname":"van de Sandt","name":"van de Sandt CE"},{"initials":"NA","lastname":"Mifsud","name":"Mifsud NA"},{"initials":"AT","lastname":"Nguyen","name":"Nguyen AT"},{"initials":"C","lastname":"Szeto","name":"Szeto C"},{"initials":"BY","lastname":"Chua","name":"Chua BY"},{"initials":"H","lastname":"Halim","name":"Halim H"},{"initials":"S","lastname":"Rizzetto","name":"Rizzetto S"},{"initials":"F","lastname":"Luciani","name":"Luciani F"},{"initials":"L","lastname":"Loh","name":"Loh L"},{"initials":"EJ","lastname":"Grant","name":"Grant EJ"},{"initials":"PM","lastname":"Saunders","name":"Saunders PM"},{"initials":"AG","lastname":"Brooks","name":"Brooks AG"},{"initials":"S","lastname":"Rockman","name":"Rockman S"},{"initials":"TC","lastname":"Kotsimbos","name":"Kotsimbos TC"},{"initials":"AC","lastname":"Cheng","name":"Cheng AC"},{"initials":"M","lastname":"Richards","name":"Richards M"},{"initials":"GP","lastname":"Westall","name":"Westall GP"},{"initials":"LM","lastname":"Wakim","name":"Wakim LM"},{"initials":"T","lastname":"Loudovaris","name":"Loudovaris T"},{"initials":"SI","lastname":"Mannering","name":"Mannering SI"},{"initials":"M","lastname":"Elliott","name":"Elliott M"},{"initials":"SG","lastname":"Tangye","name":"Tangye SG"},{"initials":"DC","lastname":"Jackson","name":"Jackson DC"},{"initials":"KL","lastname":"Flanagan","name":"Flanagan KL"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"J","lastname":"Davies","name":"Davies J"},{"initials":"A","lastname":"Miller","name":"Miller A"},{"initials":"SYC","lastname":"Tong","name":"Tong SYC"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"K","lastname":"Kedzierska","name":"Kedzierska K"}],"identifier":[{"id":"10.1038/s41467-021-23212-x","type":"doi"},{"id":"34006841","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Nat Commun","name":""},"pages":["2931"],"title":"CD8<sub>+</sub> T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph.","type":"article","url":"http://www.nature.com/articles/s41467-021-23212-x","volume":["12"],"year":[2021]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"2.16","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/6xqa"},"rcsb":{"url":"https://www.rcsb.org/structure/6xqa"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*24:02 binding \"TYQWVLKNL\" at 2.16&#8491; resolution","unique_chain_count":3}}