TNFRSF21

protein-coding

TNF receptor superfamily member 21, the group of CD molecules|Tumor necrosis factor receptor superfamily

Gene summary

This gene encodes a member of the tumor necrosis factor receptor superfamily. The encoded protein activates nuclear factor kappa-B and mitogen-activated protein kinase 8 (also called c-Jun N-terminal kinase 1), and induces cell apoptosis. Through its death domain, the encoded receptor interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD) protein, which is known to mediate signal transduction of tumor necrosis factor receptors. Knockout studies in mice suggest that this gene plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. [provided by RefSeq, Jul 2013]

MANE transcript

NM_014452.5

Inheritance

ClinVar variants

U:92B:10

Top phenotype

TNFRSF21-related condition

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr6:47,231,532-47,309,905

External References & Databases

Ensembl (ENSG00000146072)

Transcript & Mutation Effects

hg38 • Region Span ~78.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001384

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNFRSF21 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 90

TNFRSF21-related conditionTotal: 7

not providedTotal: 6

TNFRSF21-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014452.5. 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	2 clinvar	2 clinvar	5
missense			91 clinvar	5 clinvar	1 clinvar	97
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	92	7	3	102

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014452.5	RefSeq	NP_055267.1	6	MANE Select
ENST00000296861.2	Ensembl	ENSP00000296861.2	6	MANE Select
ENST00000877798.1	Ensembl	ENSP00000547857.1	7	Standard
ENST00000877798.2	Ensembl	ENSP00000547857.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tnfrsf21	Danio rerio	Structure: central artery Quality: decreased branchiness abnormal

Gene / Model

Organism

Observed Phenotype

tnfrsf21

Danio rerio

Structure: central artery

Quality: decreased branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytokine-cytokine receptor interaction - Homo sapiens (human)
Apoptosis
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
Apoptosis-related network due to altered Notch3 in ovarian cancer
Cellular response to heat stress

Biological Process

B cell apoptotic process
adaptive immune response
apoptotic process
humoral immune response
axonal fasciculation

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
axon
intrinsic component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296861
Coding exons: 6
Length: 78374
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.22	304	370	0.822	0.0000218	4260
Missense (PolyPhen)		85	141.55	0.6005		1623
Synonymous	-0.288	158	153	1.03	0.00000941	1348
Loss of Function	2.84	6	19.6	0.307	9.27e-7	247

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.00014	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B. Can also promote apoptosis mediated by BAX and by the release of cytochrome c from the mitochondria into the cytoplasm. Plays a role in neuronal apoptosis, including apoptosis in response to amyloid peptides derived from APP, and is required for both normal cell body death and axonal pruning. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). N-APP binds TNFRSF21; this triggers caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase- 6). Negatively regulates oligodendrocyte survival, maturation and myelination. Plays a role in signaling cascades triggered by stimulation of T-cell receptors, in the adaptive immune response and in the regulation of T-cell differentiation and proliferation. Negatively regulates T-cell responses and the release of cytokines such as IL4, IL5, IL10, IL13 and IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and IgM in response to antigens. May inhibit the activation of JNK in response to T-cell stimulation. {ECO:0000269|PubMed:21725297, ECO:0000269|PubMed:22761420, ECO:0000269|PubMed:9714541}.;

Recessive Scores

pRec: 0.228

Intolerance Scores

LoFtool: 0.0511
RVIS EVS: -1
RVIS percentile EVS: 8.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.824

Gene Damage Prediction

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