TNFSF4

protein-coding

TNF superfamily member 4, the group of CD molecules|Tumor necrosis factor superfamily

Gene summary

This gene encodes a cytokine of the tumor necrosis factor (TNF) ligand family. The encoded protein functions in T cell antigen-presenting cell (APC) interactions and mediates adhesion of activated T cells to endothelial cells. Polymorphisms in this gene have been associated with Sjogren's syndrome and systemic lupus erythematosus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Previous symbols:

TXGP1

MANE transcript

NM_003326.5

Inheritance

ClinVar variants

U:12B:4

Top phenotype

systemic lupus erythematosus

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr1:173,162,645-173,477,583

External References & Databases

Ensembl (ENSG00000117586)

Transcript & Mutation Effects

hg38 • Region Span ~314.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

myocardial infarction, susceptibility toLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012039

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNFSF4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 13

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003326.5. 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				2 clinvar	1 clinvar	3
missense			12 clinvar	1 clinvar		13
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	12	3	1	16

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003326.5	RefSeq	NP_003317.1	3	MANE Select
ENST00000281834.4	Ensembl	ENSP00000281834.3	3	MANE Select
NM_001297562.2	RefSeq	NP_001284491.1	3	Standard
ENST00000367718.5	Ensembl	ENSP00000356691.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytokine-cytokine receptor interaction - Homo sapiens (human)
Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway
Vitamin D Receptor Pathway
TNFR2 non-canonical NF-kB pathway
Cytokine Signaling in Immune system

Biological Process

defense response to nematode
acute inflammatory response
positive regulation of T cell cytokine production
regulation of adaptive immune response
positive regulation of type 2 immune response

Molecular Function

signaling receptor binding
cytokine activity
tumor necrosis factor receptor binding
protein binding
tumor necrosis factor receptor superfamily binding

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281834
Coding exons: 3
Length: 23580
Individuals with no LoFs: 125344
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125346
p: 0.00000798

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.925	68	93.1	0.730	0.00000437	1202
Missense (PolyPhen)		10	25.127	0.39798		331
Synonymous	0.580	34	38.6	0.881	0.00000180	355
Loss of Function	0.651	2	3.27	0.611	1.39e-7	39

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000010	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytokine that binds to TNFRSF4. Co-stimulates T-cell proliferation and cytokine production.;
Disease: DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:18059267}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. The upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and TNFSF4 transcripts. Increased levels of TNFSF4 are thought to augment T-cell-APC interaction and the functional consequences of T-cell activation, thereby destabilizing peripheral tolerance.;

Recessive Scores

pRec: 0.308

Intolerance Scores

LoFtool: 0.273
RVIS EVS: -0.23
RVIS percentile EVS: 36.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0681

Gene Damage Prediction

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