ATF4

protein-coding

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

Gene summary

This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein-protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication. [provided by RefSeq, Sep 2011]

Previous symbols:

TXREB

MANE transcript

NM_182810.3

Inheritance

—

ClinVar variants

U:76B:14

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr22:39,519,695-39,522,686

External References & Databases

Ensembl (ENSG00000128272)

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATF4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 75

not providedTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182810.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	2 clinvar	4 clinvar	7
missense			75 clinvar	2 clinvar	6 clinvar	83
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	76	4	10	90

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182810.3	RefSeq	NP_877962.1	2	MANE Select
ENST00000674920.3	Ensembl	ENSP00000501863.1	2	MANE Select
NM_001675.4	RefSeq	NP_001666.2	2	Standard
ENST00000337304.2	Ensembl	ENSP00000336790.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

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

Cellular Component

nucleus
nucleoplasm
cytoplasm
centrosome
dendrite membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337304
Coding exons: 2
Length: 2992
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-3.54	317	182	1.74	0.00000846	2306
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00027	0.00026	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.568

Intolerance Scores

LoFtool: 0.619
RVIS EVS: 1.02
RVIS percentile EVS: 91.02

Essentials

Essential (CRISPR): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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