CEBPA

protein-coding

CCAAT enhancer binding protein alpha, the group of CCAAT/enhancer binding proteins |Basic leucine zipper proteins

Gene summary

This intronless gene encodes a transcription factor that contains a basic leucine zipper (bZIP) domain and recognizes the CCAAT motif in the promoters of target genes. The encoded protein functions in homodimers and also heterodimers with CCAAT/enhancer-binding proteins beta and gamma. Activity of this protein can modulate the expression of genes involved in cell cycle regulation as well as in body weight homeostasis. Mutation of this gene is associated with acute myeloid leukemia. The use of alternative in-frame non-AUG (GUG) and AUG start codons results in protein isoforms with different lengths. Differential translation initiation is mediated by an out-of-frame, upstream open reading frame which is located between the GUG and the first AUG start codons. [provided by RefSeq, Dec 2013]

Previous symbols:

CEBP

MANE transcript

NM_004364.5

Inheritance

ClinVar variants

P:64U:724B:517

Top phenotype

Acute myeloid leukemia, familial

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:33,299,934-33,302,534

External References & Databases

Ensembl (ENSG00000245848)

Transcript & Mutation Effects

hg38 • Region Span ~2.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acute myeloid leukemiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: Ambry Genetics

acute myeloid leukemiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: G2P

acute myeloid leukemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: Genomics England PanelApp

acute myeloid leukemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: Labcorp Genetics (formerly Invitae)

acute myeloid leukemiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: ClinGen

CEBPA was first reported in relation to autosomal dominant acute myeloid leukemia in 2004 (Smith et al., 2004 PMID: 15575056). At least 16 unique variants (primarily frameshift but also missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 16 probands in 11 publications (PMIDs: 21455213, 30563700, 23716546, 21177436, 26162409, 19953636, 18946494, 18768433, 15902292, 15575056, 26721895). Variants in this gene segregated with disease in 15 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is primarily through a dominant negative effect. N-terminal frameshift mutations cause truncation of the 42-kD CEBPA protein and overproduction of a 30-kD which functions in a dominant negative fashion (Pabst et al., 2001 PMID: 11242107). A small set of variants have also been identified near the C-terminal end, in the basic leucine zipper region, which is predicted to disrupt the DNA binding and dimerization of CEBPA. EXPERIMENTAL EVIDENCE: 4 points This gene-disease association is supported by functional alteration of its biochemical function, its expression, and animal models. CEBPA functions as a myeloid transcription factor, acting as an important mediator of granulocytic maturation (Wang et al., 1999 PMID: 10397723). This is supported by the expression of CEBPA both in normal development and during malignancy (Scott et al., 1992 PMID: 1391942). This role in granulocytic maturation is disrupted by N-terminal frameshift mutations, as observed in non-patient H1299 cells (Pabst et al., 2008 PMID: 18768433). This is supported by mice carrying engineered Cebpa alleles, that specifically disrupt the 42-kDa wild-type protein while allowing expression of the dominant-negative 30-kDa form, which led to development of AML with complete penetrance (Kirstetter et al., 2008 PMID: 18394553).

Clinical Genomic Database (CGD)

Acute myeloid leukemia, familialAD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Surveillance and/or awareness of cancer risk may allow early diagnosis and treatment of malignancy, which may reduce morbidity and mortality

Refs: 15575056; 15902292; 18768433; 18946494; 20963938; 22066712; 23716546

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEBPA variants in ClinVar

8 Conditions Cataloged

Acute myeloid leukemiaTotal: 977

Inborn genetic diseasesTotal: 920

not providedTotal: 140

not specifiedTotal: 51

CEBPA-related disorderTotal: 42

Hereditary cancer-predisposing syndromeTotal: 37

CEBPA-related disordersTotal: 5

Autosomal dominant familial acute myeloid leukemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004364.5. 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	23 clinvar	405 clinvar	1 clinvar	430
missense	2 clinvar	6 clinvar	672 clinvar	110 clinvar	1 clinvar	791
nonsense	8 clinvar	4 clinvar	11 clinvar			23
start loss			1 clinvar			1
frameshift	28 clinvar	15 clinvar	17 clinvar			60
splice donor/acceptor (+/-2bp)						0
Total	38	26	724	515	2	1305

Highest pathogenic variant AF is 0.000054163494

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004364.5	RefSeq	NP_004355.2	1	MANE Select
ENST00000498907.3	Ensembl	ENSP00000427514.1	1	MANE Select
NM_001285829.2	RefSeq	NP_001272758.1	1	Standard
NM_001287424.2	RefSeq	NP_001274353.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cebpa	Danio rerio	Structure: myeloid lineage restricted progenitor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

cebpa

Danio rerio

Structure: myeloid lineage restricted progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Acute myeloid leukemia - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)
Transcriptional regulation of white adipocyte differentiation

Biological Process

urea cycle
negative regulation of transcription by RNA polymerase II
liver development
embryonic placenta development
generation of precursor metabolites and energy

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
nucleolus
intracellular membrane-bounded organelle
RNA polymerase II transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000498907
Coding exons: 1
Length: 2631
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.568	72	86.9	0.828	0.00000405	2254
Missense (PolyPhen)		25	45.924	0.54438		816
Synonymous	-0.0910	41	40.3	1.02	0.00000194	775
Loss of Function	1.44	0	2.43	0.00	1.03e-7	73

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, and cells of the lung and the placenta. Binds directly to the consensus DNA sequence 5'-T[TG]NNGNAA[TG]-3' acting as an activator on distinct target genes (PubMed:11242107). During early embryogenesis, plays essential and redundant functions with CEBPB. Essential for the transition from common myeloid progenitors (CMP) to granulocyte/monocyte progenitors (GMP). Critical for the proper development of the liver and the lung (By similarity). Necessary for terminal adipocyte differentiation, is required for postnatal maintenance of systemic energy homeostasis and lipid storage (By similarity). To regulate these different processes at the proper moment and tissue, interplays with other transcription factors and modulators. Downregulates the expression of genes that maintain cells in an undifferentiated and proliferative state through E2F1 repression, which is critical for its ability to induce adipocyte and granulocyte terminal differentiation. Reciprocally E2F1 blocks adipocyte differentiation by binding to specific promoters and repressing CEBPA binding to its target gene promoters. Proliferation arrest also depends on a functional binding to SWI/SNF complex (PubMed:14660596). In liver, regulates gluconeogenesis and lipogenesis through different mechanisms. To regulate gluconeogenesis, functionally cooperates with FOXO1 binding to IRE-controlled promoters and regulating the expression of target genes such as PCK1 or G6PC. To modulate lipogenesis, interacts and transcriptionally synergizes with SREBF1 in promoter activation of specific lipogenic target genes such as ACAS2. In adipose tissue, seems to act as FOXO1 coactivator accessing to ADIPOQ promoter through FOXO1 binding sites (By similarity). {ECO:0000250|UniProtKB:P05554, ECO:0000250|UniProtKB:P53566, ECO:0000269|PubMed:11242107, ECO:0000269|PubMed:14660596}.; FUNCTION: Isoform 4: Directly and specifically enhances ribosomal DNA transcription interacting with RNA polymerase I-specific cofactors and inducing histone acetylation. {ECO:0000269|PubMed:20075868}.;
Disease: DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:11242107, ECO:0000269|PubMed:12661007, ECO:0000269|PubMed:15575056}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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