PER3

period circadian regulator 3, the group of PAS domain containing

Basic information

Region (hg38): 1:7784290-7845177

Links

ENSG00000049246 ∙ NCBI:8863 ∙ OMIM:603427 ∙ HGNC:8847 ∙ Uniprot:P56645 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• advanced sleep phase syndrome (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Advanced sleep phase syndrome, familial, 3	AD	General	The clinical relevance of the condition is unclear	Neurologic	27001847

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PER3 gene.

• Inborn genetic diseases (62 variants)
• not provided (26 variants)
• Advanced sleep phase syndrome 3 (3 variants)
• not specified (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PER3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				4	4	8
missense			53	15	4	72
nonsense						0
start loss						0
frameshift		2				2
inframe indel					1	1
splice donor/acceptor (+/-2bp)			1	1		2
splice region				1		1
non coding						0
Total	0	2	54	20	9

Variants in PER3

This is a list of pathogenic ClinVar variants found in the PER3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-7784912-G-T		not specified	Uncertain significance (Oct 26, 2021)
1-7784929-G-T		PER3-related disorder	Likely benign (Oct 28, 2019)
1-7784970-C-A		not specified	Uncertain significance (Mar 28, 2023)
1-7785422-A-AT		PER3-related disorder	Likely benign (Jun 11, 2019)
1-7785437-C-T			Likely benign (Mar 06, 2018)
1-7785483-G-C		Advanced sleep phase syndrome 3	Uncertain significance (Mar 26, 2024)
1-7785507-C-T			Benign (Dec 21, 2018)
1-7785510-C-G		not specified	Uncertain significance (Jul 05, 2022)
1-7785515-C-T		not specified	Uncertain significance (Sep 29, 2022)
1-7785544-G-C		not specified	Uncertain significance (Jul 26, 2021)
1-7785554-A-G		not specified	Uncertain significance (Apr 07, 2022)
1-7785565-C-T		not specified	Uncertain significance (Jun 21, 2023)
1-7786712-G-A		PER3-related disorder	Likely benign (Aug 08, 2019)
1-7786807-A-G		not specified	Uncertain significance (Dec 31, 2023)
1-7786810-G-A		not specified	Uncertain significance (May 31, 2023)
1-7788093-A-G		not specified	Likely benign (Oct 30, 2023)
1-7788109-C-T		not specified	Uncertain significance (Jun 22, 2023)
1-7788124-G-A		not specified	Uncertain significance (Jul 11, 2023)
1-7788142-C-T		not specified	Uncertain significance (Oct 30, 2023)
1-7788143-G-A		PER3-related disorder	Likely benign (May 21, 2019)
1-7788196-C-T		not specified	Uncertain significance (Dec 21, 2022)
1-7793969-A-C		not specified	Uncertain significance (Jul 15, 2021)
1-7793984-T-G		not specified	Uncertain significance (Jan 04, 2024)
1-7798562-C-G		not specified	Uncertain significance (Dec 16, 2022)
1-7798577-C-G		not specified	Uncertain significance (Feb 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PER3	protein_coding	protein_coding	ENST00000361923	21	60858

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.37e-17	0.970	125567	0	181	125748	0.000720

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.109	701	693	1.01	0.0000399	7817
Missense in Polyphen		109	116.4	0.93646		1283
Synonymous	-1.26	314	287	1.09	0.0000193	2377
Loss of Function	2.53	36	56.5	0.637	0.00000280	667

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00115	0.00114
Ashkenazi Jewish	0.00	0.00
East Asian	0.00109	0.00109
Finnish	0.000324	0.000323
European (Non-Finnish)	0.000759	0.000747
Middle Eastern	0.00109	0.00109
South Asian	0.00125	0.00121
Other	0.000662	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Originally described as a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. Has a redundant role with the other PER proteins PER1 and PER2 and is not essential for the circadian rhythms maintenance. In contrast, plays an important role in sleep-wake timing and sleep homeostasis probably through the transcriptional regulation of sleep homeostasis-related genes, without influencing circadian parameters. Can bind heme. {ECO:0000269|PubMed:17346965, ECO:0000269|PubMed:19716732, ECO:0000269|PubMed:24439663, ECO:0000269|PubMed:24577121, ECO:0000269|PubMed:26903630}.
• Disease: DISEASE: Advanced sleep phase syndrome, familial, 3 (FASPS3) [MIM:616882]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269|PubMed:26903630}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Circadian rhythm - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Melatonin metabolism and effects (Consensus)

Intolerance Scores

• loftool: 0.978
• rvis_EVS: 1.35
• rvis_percentile_EVS: 94.36

Haploinsufficiency Scores

• pHI: 0.180
• hipred: N
• hipred_score: 0.429
• ghis: 0.437

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.957

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Per3
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); vision/eye phenotype

Zebrafish Information Network

• Gene name: per3
• Affected structure: circadian regulation of gene expression
• Phenotype tag: abnormal
• Phenotype quality: process quality

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;response to light stimulus;circadian regulation of gene expression;entrainment of circadian clock by photoperiod;regulation of circadian sleep/wake cycle, sleep;protein stabilization
• Cellular component: nucleus;cytoplasm
• Molecular function: transcription regulatory region sequence-specific DNA binding;transcription corepressor binding;protein binding;transcription factor binding;kinase binding;ubiquitin protein ligase binding