CREB3L1

cAMP responsive element binding protein 3 like 1, the group of CREB3 transcription factor family

Basic information

Region (hg38): 11:46277661-46321409

Links

ENSG00000157613 ∙ NCBI:90993 ∙ OMIM:616215 ∙ HGNC:18856 ∙ Uniprot:Q96BA8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• osteogenesis imperfecta type 16 (Moderate), mode of inheritance: AR
• osteogenesis imperfecta type 3 (Supportive), mode of inheritance: AD
• osteogenesis imperfecta type 16 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Osteogenesis imperfecta, type XVI	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Musculoskeletal	24079343; 30657919

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CREB3L1 gene.

• not provided (2 variants)
• Osteogenesis imperfecta type 16 (2 variants)
• Osteogenesis imperfecta (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CREB3L1 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			1	68	4	73
missense			100	7	4	111
nonsense	1		1			2
start loss						0
frameshift	2	1	2		1	6
inframe indel	1					1
splice donor/acceptor (+/-2bp)		1				1
splice region			4	6	3	13
non coding			2	38	19	59
Total	4	2	106	113	28

Highest pathogenic variant AF is 0.00000657

Variants in CREB3L1

This is a list of pathogenic ClinVar variants found in the CREB3L1 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-46277758-C-G			Benign (Oct 09, 2018)
11-46278120-C-A			Likely benign (Aug 11, 2023)
11-46278131-C-A			Uncertain significance (Jan 15, 2022)
11-46278138-G-A			Likely benign (Aug 31, 2022)
11-46278144-C-T			Likely benign (Mar 08, 2023)
11-46278147-G-A			Likely benign (May 29, 2023)
11-46278156-C-T			Likely benign (Aug 19, 2023)
11-46278157-G-T			Uncertain significance (Jun 13, 2017)
11-46278174-C-T			Likely benign (May 22, 2023)
11-46278178-G-C			Uncertain significance (Mar 09, 2022)
11-46278189-C-T			Likely benign (Sep 15, 2021)
11-46278221-G-A			Likely benign (Jul 17, 2023)
11-46296481-C-G			Benign (Jan 19, 2024)
11-46299684-C-G			Benign (Aug 09, 2018)
11-46299917-C-T			Likely benign (Mar 01, 2022)
11-46299936-A-G			Uncertain significance (Jun 12, 2022)
11-46299964-G-A		Osteogenesis imperfecta type 16	Likely benign (Feb 23, 2023)
11-46299965-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
11-46300016-C-T		Inborn genetic diseases	Uncertain significance (Jan 19, 2022)
11-46300043-T-A		Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
11-46300068-C-T		Inborn genetic diseases	Uncertain significance (Jan 29, 2024)
11-46300070-C-T		Inborn genetic diseases	Uncertain significance (Jul 25, 2023)
11-46300084-G-A			Likely benign (Apr 10, 2023)
11-46300093-C-T			Likely benign (Dec 01, 2023)
11-46300104-G-C			Uncertain significance (Jun 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CREB3L1	protein_coding	protein_coding	ENST00000529193	12	43761

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.985	0.0151	124639	0	6	124645	0.0000241

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.949	243	288	0.843	0.0000164	3322
Missense in Polyphen		72	96.25	0.74805		1173
Synonymous	0.962	117	131	0.893	0.00000881	1019
Loss of Function	3.90	2	21.5	0.0929	0.00000107	260

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000942	0.0000942
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000557	0.0000556
Finnish	0.00	0.00
European (Non-Finnish)	0.0000357	0.0000265
Middle Eastern	0.0000557	0.0000556
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor involved in unfolded protein response (UPR). Binds the DNA consensus sequence 5'-GTGXGCXGC-3' (PubMed:21767813). In the absence of endoplasmic reticulum (ER) stress, inserted into ER membranes, with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane. In response to ER stress, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus to effect transcription of specific target genes. Plays a critical role in bone formation through the transcription of COL1A1, and possibly COL1A2, and the secretion of bone matrix proteins. Directly binds to the UPR element (UPRE)-like sequence in an osteoblast-specific COL1A1 promoter region and induces its transcription. Does not regulate COL1A1 in other tissues, such as skin (By similarity). Required to protect astrocytes from ER stress-induced cell death. In astrocytes, binds to the cAMP response element (CRE) of the BiP/HSPA5 promoter and participate in its transcriptional activation (By similarity). Required for TGFB1 to activate genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). {ECO:0000250|UniProtKB:Q9Z125, ECO:0000269|PubMed:12054625, ECO:0000269|PubMed:21767813, ECO:0000269|PubMed:25310401}.
• Disease: DISEASE: Osteogenesis imperfecta 16 (OI16) [MIM:616229]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI16 is a severe form. {ECO:0000269|PubMed:24079343}. Note=The disease may be caused by mutations affecting the gene represented in this entry. OI16 affected patients show a genomic deletion encompassing CREB3L1 and the first exon of DGKZ. The absence of this exon does not affect all DGKZ isoforms, some are still produced at normal level. It cannot be ruled out that DGKZ could contribute to the phenotype, but in view of its role in bone formation, CREB3L1 is a strong OI16-causing candidate (PubMed:24079343). This hypothesis is corroborated by the observation of CREB3L1 knockout mice which exhibit features reminiscent of severe human osteogenesis imperfecta. {ECO:0000269|PubMed:24079343}.
• 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);Dopaminergic synapse - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);Vasopressin-regulated water reabsorption - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Thermogenesis - 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);cAMP signaling pathway - Homo sapiens (human);Estrogen 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);Cholinergic synapse - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;miRNA regulation of prostate cancer signaling pathways;PI3K-Akt Signaling Pathway;G1 to S cell cycle control;Unfolded Protein Response (UPR);Metabolism of proteins;CREB3 factors activate genes (Consensus)

Recessive Scores

• pRec: 0.138

Intolerance Scores

• rvis_EVS: 0.29
• rvis_percentile_EVS: 71.5

Haploinsufficiency Scores

• pHI: 0.563
• hipred: Y
• hipred_score: 0.594
• ghis: 0.392

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• gene_indispensability_pred: E
• gene_indispensability_score: 0.721

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Creb3l1
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;osteoblast differentiation;multicellular organism development;negative regulation of gene expression;endoplasmic reticulum unfolded protein response;positive regulation of collagen biosynthetic process;negative regulation of fibroblast growth factor receptor signaling pathway;negative regulation of transcription, DNA-templated;extracellular matrix constituent secretion;negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway;negative regulation of sprouting angiogenesis;positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress
• Cellular component: nuclear chromatin;nucleus;endoplasmic reticulum;endoplasmic reticulum membrane;membrane;integral component of membrane
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;protein binding;cAMP response element binding;transcription regulatory region DNA binding;SMAD binding