A20 haploinsufficiency

Summary

A20 haploinsufficiency (MONDO:0100222) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	A20 haploinsufficiency
Mondo ID	MONDO:0100222
UMLS	C5849639
MedGen	1845429
GARD	0026086
Is cancer (heuristic)	no

Also known as: HA20

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › A20 haploinsufficiency

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
135335	NM_001270508.2(TNFAIP3):c.619A>C (p.Ile207Leu)	LOC126859807	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
135331	NM_001270508.2(TNFAIP3):c.322A>G (p.Thr108Ala)	TNFAIP3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFAIP3	Orphanet:536	Systemic lupus erythematosus
TNFAIP3	Orphanet:674762	Early-onset autoinflammatory syndrome due to A20 haploinsufficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNFAIP3	HGNC:11896	ENSG00000118503	P21580	Tumor necrosis factor alpha-induced protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFAIP3	Tumor necrosis factor alpha-induced protein 3	Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFAIP3	Transcription factor	no		Znf_A20, OTU_dom, OTU_Deubiquitinase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of paranasal sinus	1
vena cava	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFAIP3	274	ubiquitous	marker	vena cava, mucosa of paranasal sinus, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFAIP3	3,716

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFAIP3	P21580	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR1-induced proapoptotic signaling	1	439.2×	0.004	TNFAIP3
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.004	TNFAIP3
Negative regulators of DDX58/IFIH1 signaling	1	326.3×	0.004	TNFAIP3
NOD1/2 Signaling Pathway	1	317.2×	0.004	TNFAIP3
Ovarian tumor domain proteases	1	278.5×	0.004	TNFAIP3
Regulation of TNFR1 signaling	1	223.9×	0.004	TNFAIP3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of toll-like receptor 5 signaling pathway	1	16852.0×	7e-04	TNFAIP3
regulation of vascular wound healing	1	16852.0×	7e-04	TNFAIP3
negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway	1	16852.0×	7e-04	TNFAIP3
establishment of protein localization to vacuole	1	16852.0×	7e-04	TNFAIP3
negative regulation of CD40 signaling pathway	1	8426.0×	0.001	TNFAIP3
negative regulation of chronic inflammatory response	1	5617.3×	0.001	TNFAIP3
tolerance induction to lipopolysaccharide	1	5617.3×	0.001	TNFAIP3
negative regulation of osteoclast proliferation	1	5617.3×	0.001	TNFAIP3
B-1 B cell homeostasis	1	4213.0×	0.001	TNFAIP3
negative regulation of toll-like receptor 3 signaling pathway	1	4213.0×	0.001	TNFAIP3
negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	1	4213.0×	0.001	TNFAIP3
regulation of germinal center formation	1	2808.7×	0.001	TNFAIP3
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	2808.7×	0.001	TNFAIP3
negative regulation of toll-like receptor 2 signaling pathway	1	2407.4×	0.001	TNFAIP3
negative regulation of B cell activation	1	2407.4×	0.001	TNFAIP3
response to molecule of bacterial origin	1	2106.5×	0.001	TNFAIP3
regulation of defense response to virus by host	1	2106.5×	0.001	TNFAIP3
positive regulation of hepatocyte proliferation	1	1685.2×	0.002	TNFAIP3
protein K11-linked deubiquitination	1	1532.0×	0.002	TNFAIP3
response to muramyl dipeptide	1	1404.3×	0.002	TNFAIP3
protein deubiquitination involved in ubiquitin-dependent protein catabolic process	1	1296.3×	0.002	TNFAIP3
negative regulation of toll-like receptor 4 signaling pathway	1	1123.5×	0.002	TNFAIP3
negative regulation of bone resorption	1	991.3×	0.002	TNFAIP3
regulation of tumor necrosis factor-mediated signaling pathway	1	702.2×	0.003	TNFAIP3
protein K48-linked deubiquitination	1	648.1×	0.003	TNFAIP3
negative regulation of smooth muscle cell proliferation	1	624.1×	0.003	TNFAIP3
protein K63-linked deubiquitination	1	624.1×	0.003	TNFAIP3
negative regulation of interleukin-2 production	1	581.1×	0.003	TNFAIP3
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	581.1×	0.003	TNFAIP3
negative regulation of interleukin-1 beta production	1	510.7×	0.003	TNFAIP3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNFAIP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TNFAIP3	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TNFAIP3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFAIP3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.