TNFRSF1A

TNF receptor superfamily member 1A, the group of CD molecules|Tumor necrosis factor receptor superfamily

Basic information

Region (hg38): 12:6328757-6342114

Previous symbols: [ "TNFR1" ]

Links

ENSG00000067182 ∙ NCBI:7132 ∙ OMIM:191190 ∙ HGNC:11916 ∙ Uniprot:P19438 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant familial periodic fever (Definitive), mode of inheritance: AD
• autosomal dominant familial periodic fever (Strong), mode of inheritance: AD
• autosomal dominant familial periodic fever (Supportive), mode of inheritance: AD
• autosomal dominant familial periodic fever (Definitive), mode of inheritance: AD
• autosomal dominant familial periodic fever (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Periodic fever, familial, autosomal dominant	AD	Allergy/Immunology/Infectious	Individuals may manifest with sequelae such as periodic fever, pain, and rash, and medical treatment with TNF inhibitors (eg, etanercept) has been reported as effective in many individuals	Allergy/Immunology/Infectious; Dermatologic; Neurologic	1402641; 9585614; 9529351; 10199409; 10412980; 11115159; 11175303; 12584543; 17360963; 19381634; 21153346; 21225694; 21378401; 21869706; 22675839; 22281876

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TNFRSF1A gene.

• TNF receptor-associated periodic fever syndrome (TRAPS) (6 variants)
• not provided (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TNFRSF1A 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			4	87	1	92
missense	6	16	160	13		195
nonsense						0
start loss						0
frameshift		1	2			3
inframe indel			4			4
splice donor/acceptor (+/-2bp)		1	1			2
splice region			8	19		27
non coding			18	61	31	110
Total	6	18	189	161	32

Variants in TNFRSF1A

This is a list of pathogenic ClinVar variants found in the TNFRSF1A region.

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

Position	Type	Phenotype	Significance	ClinVar
12-6328918-T-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 13, 2018)
12-6328925-T-C		TNF receptor-associated periodic fever syndrome (TRAPS)	Likely benign (Apr 27, 2017)
12-6328935-AAAAAC-A		Familial Periodic Fever	Uncertain significance (Jun 14, 2016)
12-6328935-A-AAAAAC		Familial Periodic Fever	Uncertain significance (Jun 14, 2016)
12-6328938-A-C		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 12, 2018)
12-6328961-C-CA		Familial Periodic Fever	Likely benign (Jun 14, 2016)
12-6328979-C-T		TNF receptor-associated periodic fever syndrome (TRAPS)	Benign (Jan 13, 2018)
12-6329015-C-T		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 13, 2018)
12-6329049-G-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 12, 2018)
12-6329060-T-C		TNF receptor-associated periodic fever syndrome (TRAPS)	Conflicting classifications of pathogenicity (May 01, 2023)
12-6329117-C-T		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 13, 2018)
12-6329134-G-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 12, 2018)
12-6329164-G-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 13, 2018)
12-6329248-A-G		TNF receptor-associated periodic fever syndrome (TRAPS)	Conflicting classifications of pathogenicity (Jan 12, 2018)
12-6329274-G-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 13, 2018)
12-6329290-A-G			Benign (Mar 03, 2015)
12-6329313-C-T		TNF receptor-associated periodic fever syndrome (TRAPS)	Likely benign (Oct 03, 2023)
12-6329317-T-G		TNF receptor-associated periodic fever syndrome (TRAPS)	Likely benign (Dec 22, 2023)
12-6329321-A-C		TNF receptor-associated periodic fever syndrome (TRAPS)	Likely benign (May 19, 2023)
12-6329324-A-T		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Jan 13, 2018)
12-6329326-T-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Oct 13, 2022)
12-6329329-G-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Uncertain significance (Feb 10, 2022)
12-6329331-G-C		TNF receptor-associated periodic fever syndrome (TRAPS) • Autoinflammatory syndrome	Uncertain significance (Jan 07, 2022)
12-6329336-C-A		TNF receptor-associated periodic fever syndrome (TRAPS)	Likely benign (Dec 11, 2023)
12-6329336-C-T		TNF receptor-associated periodic fever syndrome (TRAPS)	Likely benign (May 07, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TNFRSF1A	protein_coding	protein_coding	ENST00000162749	10	13358

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.995	0.00510	125687	0	3	125690	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.10	170	267	0.638	0.0000172	2904
Missense in Polyphen		37	95.447	0.38765		1024
Synonymous	0.250	115	118	0.971	0.00000839	904
Loss of Function	3.94	1	20.1	0.0498	9.52e-7	254

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.00000889	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate- specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.
• Disease: DISEASE: Familial hibernian fever (FHF) [MIM:142680]: A hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases. {ECO:0000269|PubMed:10199409, ECO:0000269|PubMed:10902757, ECO:0000269|PubMed:11443543, ECO:0000269|PubMed:13130484, ECO:0000269|PubMed:14610673}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple sclerosis 5 (MS5) [MIM:614810]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269|PubMed:22801493}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist.
• Pathway: mTOR signaling pathway - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Apoptosis - multiple species - Homo sapiens (human);Influenza A - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Necroptosis - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);Tuberculosis - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Apoptosis - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Apoptosis Modulation and Signaling;Alzheimers Disease;TNF alpha Signaling Pathway;Amyotrophic lateral sclerosis (ALS);Nanoparticle triggered regulated necrosis;Apoptosis;Cardiac Hypertrophic Response;Photodynamic therapy-induced AP-1 survival signaling.;Photodynamic therapy-induced NF-kB survival signaling;Apoptotic Signaling Pathway;MAPK Signaling Pathway;Apoptosis Modulation by HSP70;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;Interleukin-10 signaling;Inflammatory Response Pathway;Signal Transduction;tnfr1 signaling pathway;hiv-1 nef: negative effector of fas and tnf;tnf/stress related signaling;nf-kb signaling pathway;keratinocyte differentiation;TNFR2 non-canonical NF-kB pathway;Cytokine Signaling in Immune system;Immune System;TNFs bind their physiological receptors;ceramide signaling pathway;TNFR1-induced NFkappaB signaling pathway;TNFR1-induced proapoptotic signaling;TNFR1-mediated ceramide production;TNF signaling;sodd/tnfr1 signaling pathway;Death Receptor Signalling;Regulation of TNFR1 signaling;TNFalpha;TNF;Canonical NF-kappaB pathway;Caspase Cascade in Apoptosis;HIV-1 Nef: Negative effector of Fas and TNF-alpha;TNF receptor signaling pathway ;Signaling events mediated by HDAC Class I;Ceramide signaling pathway (Consensus)

Recessive Scores

• pRec: 0.916

Intolerance Scores

• loftool: 0.0327
• rvis_EVS: 0.08
• rvis_percentile_EVS: 60.31

Haploinsufficiency Scores

• pHI: 0.510
• hipred: Y
• hipred_score: 0.743
• ghis: 0.457

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.603

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tnfrsf1a
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); liver/biliary system phenotype; embryo phenotype; renal/urinary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Gene ontology

• Biological process: aortic valve development;pulmonary valve development;negative regulation of extracellular matrix constituent secretion;prostaglandin metabolic process;inflammatory response;I-kappaB kinase/NF-kappaB signaling;extrinsic apoptotic signaling pathway via death domain receptors;intrinsic apoptotic signaling pathway in response to DNA damage;negative regulation of cardiac muscle hypertrophy;regulation of tumor necrosis factor-mediated signaling pathway;viral process;cytokine-mediated signaling pathway;tumor necrosis factor-mediated signaling pathway;positive regulation of tyrosine phosphorylation of STAT protein;defense response to bacterium;positive regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of transcription by RNA polymerase II;negative regulation of inflammatory response;positive regulation of inflammatory response;cellular response to mechanical stimulus;death-inducing signaling complex assembly;protein localization to plasma membrane;positive regulation of apoptotic process involved in morphogenesis;regulation of establishment of endothelial barrier;positive regulation of ceramide biosynthetic process
• Cellular component: Golgi membrane;tumor necrosis factor receptor superfamily complex;extracellular region;extracellular space;mitochondrion;plasma membrane;integral component of plasma membrane;cell surface;membrane;receptor complex;membrane raft
• Molecular function: tumor necrosis factor-activated receptor activity;protein binding;tumor necrosis factor binding