TNF

protein-coding

tumor necrosis factor, the group of Tumor necrosis factor superfamily

Gene summary

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer disease. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Aug 2020]

Previous symbols:

TNFA

MANE transcript

NM_000594.4

Inheritance

—

ClinVar variants

P:1U:10B:6

Top phenotype

Migraine with or without aura, susceptibility to, 1

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr6:31,575,565-31,578,336

External References & Databases

Ensembl (ENSG00000232810)

Transcript & Mutation Effects

hg38 • Region Span ~2.8 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 TNF variants in ClinVar

6 Conditions Cataloged

not providedTotal: 6

not specifiedTotal: 6

Migraine with or without aura, susceptibility to, 1Total: 2

Increased circulating interleukin 6 concentrationTotal: 1

TNF receptor binding, alteredTotal: 1

Inherited susceptibility to asthmaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000594.4. 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				4 clinvar	1 clinvar	5
missense	1 clinvar		9 clinvar	1 clinvar		11
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	0	10	5	1	17

Highest pathogenic variant AF is 0.000007441999

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000594.4	RefSeq	NP_000585.2	4	MANE Select
ENST00000449264.3	Ensembl	ENSP00000398698.2	4	MANE Select
ENST00000699334.1	Ensembl	ENSP00000514308.1	2	Standard
ENST00001140822.1	Ensembl	ENSP00000812782.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tnfb	Danio rerio	Structure: liver Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

tnfb

Danio rerio

Structure: liver

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
mTOR signaling pathway - Homo sapiens (human)
Type I diabetes mellitus - Homo sapiens (human)
Adipocytokine signaling pathway - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)

Biological Process

obsolete protein import into nucleus, translocation
negative regulation of transcription by RNA polymerase II
MAPK cascade
activation of MAPKKK activity
activation of MAPK activity

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
protease binding
cytokine activity
tumor necrosis factor receptor binding
protein binding

Cellular Component

phagocytic cup
extracellular region
extracellular space
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000449264
Coding exons: 4
Length: 2770
Individuals with no LoFs: 123531
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 123533
p: 0.00000809

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.62	84	137	0.611	0.00000799	1493
Missense (PolyPhen)		9	34.644	0.25978		447
Synonymous	0.845	54	62.5	0.864	0.00000378	501
Loss of Function	2.59	1	9.74	0.103	5.67e-7	98

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.00010	0.00010	rare
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: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918, PubMed:16829952, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}.;
Disease: DISEASE: Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.194
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): 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