CREB3L3

protein-coding

cAMP responsive element binding protein 3 like 3, the group of CREB3 transcription factor family

Gene summary

This gene encodes a member of the basic-leucine zipper family and the AMP-dependent transcription factor family. The encoded protein is localized to the endoplasmic reticulum and acts as a transcription factor activated by cyclic AMP stimulation. The encoded protein binds the cyclic AMP response element (CRE) and the box-B element and has been linked to acute inflammatory response, hepatocellular carcinoma, triglyceride metabolism, and hepcidin expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

MANE transcript

NM_032607.3

Inheritance

ClinVar variants

P:23U:156B:94

Top phenotype

Hypertriglyceridemia 2

gnomAD constraint

pLI —, LoF o/e 1.01

Max pathogenic AF

—

Genomic locus

chr19:4,153,631-4,173,054

External References & Databases

Ensembl (ENSG00000060566)

Transcript & Mutation Effects

hg38 • Region Span ~19.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypertriglyceridemia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859149

Submitter: Labcorp Genetics (formerly Invitae)

hypertriglyceridemia 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859149

Submitter: Ambry Genetics

hypertriglyceridemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005347

Submitter: Genomics England PanelApp

hypertriglyceridemia 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007788

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypertriglyceridemia 2AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The condition can involve hypertriglyceridemia, and management via diet and omega-3 fatty acid therapy has been described as beneficial

Refs: 26427795; 29954705

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CREB3L3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 270

not specifiedTotal: 87

CREB3L3-related disorderTotal: 17

Hypertriglyceridemia 2Total: 13

Hypertriglyceridemia 1Total: 2

Episodic kinesigenic dyskinesia 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032607.3. 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			3 clinvar	66 clinvar	5 clinvar	74
missense		1 clinvar	140 clinvar	22 clinvar	1 clinvar	164
nonsense	5 clinvar	5 clinvar	2 clinvar			12
start loss						0
frameshift	6 clinvar	2 clinvar	3 clinvar			11
splice donor/acceptor (+/-2bp)		4 clinvar	8 clinvar			12
Total	11	12	156	88	6	273

Highest pathogenic variant AF is 0.000042148742

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032607.3	RefSeq	NP_115996.1	10	MANE Select
ENST00000078445.7	Ensembl	ENSP00000078445.1	10	MANE Select
NM_001271995.2	RefSeq	NP_001258924.1	10	Standard
NM_001271996.2	RefSeq	NP_001258925.1	10	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)
Dopaminergic synapse - Homo sapiens (human)

Biological Process

positive regulation of acute inflammatory response
endoplasmic reticulum unfolded protein response
positive regulation of transcription by RNA polymerase II
positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress

Molecular Function

transcription regulatory region sequence-specific DNA binding
RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
protein binding

Cellular Component

Golgi membrane
nucleus
nucleoplasm
endoplasmic reticulum
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000078445
Coding exons: 10
Length: 19454
Individuals with no LoFs: 125569
Homozygous LoFs: 0
Heterozygous LoFs: 179
Defined: 125748
p: 0.000712

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.249	258	270	0.957	0.0000168	2950
Missense (PolyPhen)		74	81.201	0.91132		955
Synonymous	-1.81	149	123	1.21	0.00000868	990
Loss of Function	-0.0484	20	19.8	1.01	0.00000109	210

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.0015	0.0015	notable
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00079	0.00079	rare
South Asian	0.00020	0.00020	rare
Other	0.0021	0.0021	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes. Activated in response to cAMP stimulation. In vitro, binds to the cAMP response element (CRE) and box-B element. Activates transcription through box-B element. Activates transcription through CRE (By similarity). Seems to function synergistically with ATF6. In acute inflammatory response, may activate expression of acute phase response (APR) genes. May be involved in growth suppression. {ECO:0000250, ECO:0000269|PubMed:11353085, ECO:0000269|PubMed:15800215, ECO:0000269|PubMed:16469704}.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.262
RVIS EVS: -0.71
RVIS percentile EVS: 14.67

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.433

Gene Damage Prediction

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