PER3

Chr 1AD

period circadian regulator 3

Also known as: FASPS3, GIG13

NCBI Gene: 8863 ENSG00000049246 UniProt: P56645 OMIM: 603427

The PER3 protein is a component of the circadian clock system that functions in a transcriptional feedback loop to regulate circadian rhythms and plays an important role in sleep-wake timing and sleep homeostasis. Polymorphisms in this gene have been linked to sleep disorders, though the gene is not highly constrained against loss-of-function variants. The inheritance pattern for PER3-related sleep disorders has not been clearly established from the available data.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been linked to sleep disorders. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Advanced sleep phase syndrome, familial, 3MIM #616882

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.84

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.53

OE 0.64 (0.49–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.11Z-score

OE missense 1.01 (0.95–1.08)

701 obs / 693.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.64 (0.49–0.84)

0≤0.351.4

Missense OE?1.01 (0.95–1.08)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 36 / 56.5Missense obs/exp: 701 / 693.0Syn Z: -1.26

Background carrier burden — how many people carry a rare variant somewhere in PER3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 32

1,670 rare PASS variants

Rare truncating (LoF)

1 in 120

399 rare PASS variants

Rare synonymous (reference)

1 in 58

658 rare PASS variants

Rare missense and truncating variants are carried at similar rates in PER3; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 44	1 in 210
South Asian	~43k	1 in 25	1 in 120
Remaining (unassigned)	~30k	1 in 28	1 in 110
European (Finnish)	~27k	1 in 110	1 in 110
Admixed American	~22k	1 in 35	1 in 100
African / African American	~21k	1 in 28	1 in 250
East Asian	~20k	1 in 37	1 in 110
Ashkenazi Jewish	~13k	1 in 190	1 in 720
Middle Eastern	~2,884	1 in 40	1 in 550

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 21 coding exons well covered in gnomAD exomes; exons 4, 8, 9, 11, 20 marginal. Genomes: 20 of 21 (exon 19 below).? see exons ↓