TBX21

protein-coding

T-box transcription factor 21, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells. [provided by RefSeq, Jul 2008]

MANE transcript

NM_013351.2

Inheritance

ClinVar variants

P:1U:68B:8

Top phenotype

Immunodeficiency 88

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr17:47,733,236-47,746,122

External References & Databases

Ensembl (ENSG00000073861)

Transcript & Mutation Effects

hg38 • Region Span ~12.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 88LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030483

Submitter: PanelApp Australia

immunodeficiency 88LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030483

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 88MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030483

Submitter: LiferaOmics

Genetic evidence – Published PMID: 33296702 – Family 1 – one proband. Case-level (AR homozygous predicted null del/ins variant; loss-of-function mechanism established; consanguineous family; −0.5 consanguinity deduction applied) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Published genetic evidence total = 1.0 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous; no consanguinity deduction applied [consanguinity not documented]) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 Total genetic evidence (published AR + our cases) 1.0 (published AR) + 1.5 (our case) = 2.5 / 12 Experimental evidence – Published PMID: 33296702 – Functional alteration (patient and non-patient cells). The pathogenic TBX21 variant impaired protein production, nuclear localization, and DNA binding; patient primary CD4+ T cells demonstrated abnormal downstream target gene expression (including IFNG) and impaired effector cytokine production; defects were also observed in NK, MAIT, and innate-like lymphocyte subsets. Functional alteration (strong patient-cell evidence supporting AR loss-of-function mechanism) = 1.5 PMID: 34160550 – Functional rescue and regulatory studies. The pathogenic TBX21 variant failed to suppress Th2 cytokine production, with altered chromatin accessibility; expression of wild-type TBX21 rescued the phenotype in vitro. Functional alteration / rescue (additional mechanistic support; same patient and mutation) = 1.0 PMID: 16177104 – Tbx21 knockout mouse model. Tbx21-deficient mice showed increased susceptibility to Mycobacterium tuberculosis with diminished Th1 responses and reduced Ifng production, supporting a role for TBX21 in IFN-γ–mediated antimycobacterial immunity. Model system (animal model recapitulating disease-relevant immune defect) = 2.0 Experimental evidence total = 4.5 / 6 Overall score Genetic evidence = 2.5 Experimental evidence = 4.5 Overall score = 7.0 / 18

asthma, nasal polyps, and aspirin intoleranceLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008834

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 88AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described as having increased risk of mycobacterial infection, and awareness may allow preventative measures (eg, related to vaccinations) and early and aggressive treatment

Refs: 33296702; 34160550

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX21 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 66

Immunodeficiency 88Total: 7

TBX21-related disorderTotal: 7

Asthma, nasal polyps, and aspirin intoleranceTotal: 6

not providedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013351.2. 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				6 clinvar		6
missense	1 clinvar		68 clinvar	2 clinvar		71
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	68	8	0	77

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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_013351.2	RefSeq	NP_037483.1	6	MANE Select
ENST00000177694.2	Ensembl	ENSP00000177694.1	6	MANE Select
ENST00000906368.1	Ensembl	ENSP00000576427.1	7	Standard
ENST00000996922.1	Ensembl	ENSP00000666739.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory bowel disease (IBD) - Homo sapiens (human)
Th17 cell differentiation - Homo sapiens (human)
Th1 and Th2 cell differentiation - Homo sapiens (human)
Endoderm Differentiation
Development and heterogeneity of the ILC family

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription, DNA-templated
multicellular organism development
response to virus
T cell differentiation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding
sequence-specific DNA binding

Cellular Component

nucleus
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000177694
Coding exons: 6
Length: 12876
Individuals with no LoFs: 125745
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125748
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.40	222	289	0.769	0.0000164	3440
Missense (PolyPhen)		78	127	0.61417		1479
Synonymous	0.784	106	117	0.908	0.00000670	1093
Loss of Function	4.04	1	21.0	0.0477	0.00000109	231

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs (PubMed:10761931). Activates transcription of a set of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. Activates IFNG and CXCR3 genes in part by recruiting chromatin remodeling complexes including KDM6B, a SMARCA4- containing SWI/SNF-complex, and an H3K4me2-methyltransferase complex to their promoters and all of these complexes serve to establish a more permissive chromatin state conducive with transcriptional activation (By similarity). Can activate Th1 genes also via recruitment of Mediator complex and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) in the form of the super elongation complex (SEC) to super-enhancers and associated genes in activated Th1 cells (PubMed:27292648). Inhibits the Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of Th17 cell-specific transcriptinal regulator RORC. Inhibits the Th2 cell lineage commitment by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and IL- 13, via repression of transcriptional regulators GATA3 and NFATC2. Protects Th1 cells from amplifying aberrant type-I IFN response in an IFN-gamma abundant microenvironment by acting as a repressor of type-I IFN transcription factors and type-I IFN-stimulated genes. Acts as a regulator of antiviral B-cell responses; controls chronic viral infection by promoting the antiviral antibody IgG2a isotype switching and via regulation of a broad antiviral gene expression program (By similarity). {ECO:0000250|UniProtKB:Q9JKD8, ECO:0000269|PubMed:10761931, ECO:0000269|PubMed:27292648}.;
Disease: DISEASE: Asthma, with nasal polyps and aspirin intolerance (ANPAI) [MIM:208550]: A condition consisting of asthma, aspirin sensitivity and nasal polyposis. Nasal polyposis is due to chronic inflammation of the paranasal sinus mucosa, leading to protrusion of edematous polyps into the nasal cavities. {ECO:0000269|PubMed:15806396}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.552

Intolerance Scores

LoFtool: 0.0673
RVIS EVS: -0.74
RVIS percentile EVS: 13.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.803

Gene Damage Prediction

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