ATF4

activating transcription factor 4, the group of Basic leucine zipper proteins

Basic information

Region (hg38): 22:39519695-39522686

Previous symbols: [ "TXREB" ]

Links

ENSG00000128272 ∙ NCBI:468 ∙ OMIM:604064 ∙ HGNC:786 ∙ Uniprot:P18848 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATF4 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATF4 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				2	4	6
missense			26	2	6	34
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	26	4	10

Variants in ATF4

This is a list of pathogenic ClinVar variants found in the ATF4 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-39521452-G-A			Benign (Dec 31, 2019)
22-39521534-G-A		not specified	Uncertain significance (May 23, 2023)
22-39521618-C-T		not specified	Uncertain significance (Sep 29, 2023)
22-39521779-C-T		not specified	Uncertain significance (Aug 01, 2023)
22-39521782-T-G		not specified	Uncertain significance (Jun 09, 2022)
22-39521786-C-T			Benign (Jun 18, 2018)
22-39521794-A-T		not specified	Uncertain significance (Jan 27, 2022)
22-39521859-C-G		not specified	Uncertain significance (Aug 10, 2023)
22-39521875-A-G		not specified	Uncertain significance (Sep 14, 2023)
22-39521899-A-C		not specified	Uncertain significance (Sep 15, 2021)
22-39521910-C-T		not specified	Uncertain significance (Jan 26, 2022)
22-39521919-C-T		not specified	Uncertain significance (Dec 19, 2023)
22-39521939-T-C			Benign (Dec 31, 2019)
22-39521947-C-A		not specified	Uncertain significance (Sep 22, 2023)
22-39521950-C-T			Benign (Dec 31, 2019)
22-39521955-A-T			Likely benign (Dec 31, 2019)
22-39521967-A-G		not specified	Uncertain significance (Dec 16, 2023)
22-39522030-C-T		not specified	Uncertain significance (Mar 07, 2024)
22-39522031-C-T		not specified	Uncertain significance (May 11, 2022)
22-39522033-C-T		not specified	Uncertain significance (Apr 13, 2023)
22-39522044-C-T			Benign (Jun 26, 2018)
22-39522060-T-C		not specified	Uncertain significance (Mar 28, 2024)
22-39522125-G-A			Likely benign (Mar 02, 2018)
22-39522142-C-T		not specified	Uncertain significance (Sep 06, 2022)
22-39522146-C-T			Benign (Dec 31, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATF4	protein_coding	protein_coding	ENST00000337304	2	2992

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0157	0.890	125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-3.54	317	182	1.74	0.00000846	2306
Missense in Polyphen		78	47.973	1.6259		649
Synonymous	-5.46	135	74.9	1.80	0.00000375	682
Loss of Function	1.40	4	8.39	0.477	3.53e-7	121

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000397	0.000391
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000536	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.0000328	0.0000327
Other	0.000165	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to endoplasmic reticulum (ER) stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. During ER stress response, activates the transcription of NLRP1, possibly in concert with other factors (PubMed:26086088). {ECO:0000250, ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:18940792, ECO:0000269|PubMed:26086088}.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Cortisol synthesis and secretion - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis B - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Apoptosis - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Myometrial Relaxation and Contraction Pathways;Photodynamic therapy-induced unfolded protein response;MAPK Signaling Pathway;mRNA, protein, and metabolite inducation pathway by cyclosporin A;VEGFA-VEGFR2 Signaling Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Validated transcriptional targets of AP1 family members Fra1 and Fra2 (Consensus)

Recessive Scores

• pRec: 0.568

Intolerance Scores

• loftool: 0.619
• rvis_EVS: 1.02
• rvis_percentile_EVS: 91.02

Haploinsufficiency Scores

• pHI: 0.122
• hipred: Y
• hipred_score: 0.676
• ghis: 0.436

Essentials

• essential_gene_CRISPR: E
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atf4
• Phenotype: skeleton phenotype; digestive/alimentary 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); vision/eye phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; liver/biliary system phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan)

Gene ontology

• Biological process: gluconeogenesis;regulation of transcription, DNA-templated;regulation of transcription by RNA polymerase II;transcription by RNA polymerase II;cellular amino acid metabolic process;cellular calcium ion homeostasis;gamma-aminobutyric acid signaling pathway;response to toxic substance;positive regulation of vascular endothelial growth factor production;positive regulation of gene expression;neuron differentiation;negative regulation of translational initiation in response to stress;circadian regulation of gene expression;cellular response to amino acid starvation;cellular response to UV;response to endoplasmic reticulum stress;positive regulation of transcription from RNA polymerase II promoter in response to stress;positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress;PERK-mediated unfolded protein response;cellular response to glucose starvation;mRNA transcription by RNA polymerase II;positive regulation of apoptotic process;negative regulation of potassium ion transport;positive regulation of neuron apoptotic process;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase I;positive regulation of transcription by RNA polymerase II;positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance;intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress;positive regulation of biomineral tissue development;cellular response to oxygen-glucose deprivation;negative regulation of cold-induced thermogenesis;negative regulation of oxidative stress-induced neuron death;cellular response to dopamine;positive regulation of vascular associated smooth muscle cell apoptotic process;positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress;response to manganese-induced endoplasmic reticulum stress;positive regulation of sodium-dependent phosphate transport
• Cellular component: nucleus;nucleoplasm;cytoplasm;centrosome;dendrite membrane;protein-containing complex;nuclear periphery;neuron projection;Lewy body core;ATF4-CREB1 transcription factor complex;ATF1-ATF4 transcription factor complex;CHOP-ATF4 complex
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II transcription factor binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding;protein C-terminus binding;protein kinase binding;leucine zipper domain binding;sequence-specific DNA binding;transcription regulatory region DNA binding;protein heterodimerization activity