Immunodeficiency 39

Summary

Immunodeficiency 39 (MONDO:0014597) is a disease caused by IRF7 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IRF7 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 731

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 39
Mondo ID	MONDO:0014597
OMIM	616345
Orphanet	574918
DOID	DOID:0111969
ICD-10-CM	D84.8
SNOMED CT	1269234000
UMLS	C4225358
MedGen	904167
GARD	0025005
Is cancer (heuristic)	no

Also known as: IMD39 · immunodeficiency 39 · immunodeficiency type 39 · IRF7 primary immunodeficiency disease · predisposition to severe viral infection due to IRF7 deficiency · primary immunodeficiency disease caused by mutation in IRF7

Data availability: 731 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › immunodeficiency 39

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, 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, A20 haploinsufficiency, 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

600 retrieved; paginated sample, class counts are floors:

333 uncertain significance, 239 likely benign, 18 benign, 4 conflicting classifications of pathogenicity, 4 risk factor, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
190238	NM_001572.5(IRF7):c.1261C>T (p.Gln421Ter)	IRF7	risk factor	no assertion criteria provided
4082255	IRF7, 1-BP INS, C (rs970393690)	IRF7	risk factor	no assertion criteria provided
4082256	IRF7, 1-BP DEL, G (rs542925396)	IRF7	risk factor	no assertion criteria provided
4082257	IRF7, TRP91TER (rs1416109339)	IRF7	risk factor	no assertion criteria provided
1414685	NM_001572.5(IRF7):c.1052G>A (p.Arg351Gln)	IRF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1416264	NM_001572.5(IRF7):c.686G>A (p.Gly229Glu)	IRF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432117	NM_001572.5(IRF7):c.1453G>A (p.Ala485Thr)	IRF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2972434	NM_001572.5(IRF7):c.461C>T (p.Pro154Leu)	IRF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003051	NM_001572.5(IRF7):c.829G>A (p.Ala277Thr)	IRF7	Uncertain significance	criteria provided, single submitter
1004159	NM_001572.5(IRF7):c.109C>T (p.Arg37Cys)	IRF7	Uncertain significance	criteria provided, single submitter
1004487	NM_001572.5(IRF7):c.847+1G>C	IRF7	Uncertain significance	criteria provided, single submitter
1006115	NM_001572.5(IRF7):c.377G>A (p.Arg126Gln)	IRF7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1006409	NM_001572.5(IRF7):c.1106G>A (p.Arg369Gln)	IRF7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007718	NM_001572.5(IRF7):c.1221_1222del (p.Phe407fs)	IRF7	Uncertain significance	criteria provided, single submitter
1009507	NM_001572.5(IRF7):c.1419G>A (p.Leu473=)	IRF7	Uncertain significance	criteria provided, single submitter
1010743	NM_001572.5(IRF7):c.1452C>A (p.Ser484Arg)	IRF7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014249	NM_001572.5(IRF7):c.329A>G (p.Asp110Gly)	IRF7	Uncertain significance	criteria provided, single submitter
1015030	NM_001572.5(IRF7):c.1197C>G (p.Asn399Lys)	IRF7	Uncertain significance	criteria provided, single submitter
1016506	NM_001572.5(IRF7):c.602G>A (p.Trp201Ter)	IRF7	Uncertain significance	criteria provided, single submitter
1018212	NM_001572.5(IRF7):c.250G>A (p.Glu84Lys)	IRF7	Uncertain significance	criteria provided, single submitter
1018214	NM_001572.5(IRF7):c.738_750dup (p.Ala251fs)	IRF7	Uncertain significance	criteria provided, single submitter
1018217	NM_001572.5(IRF7):c.1184T>G (p.Leu395Arg)	IRF7	Uncertain significance	criteria provided, single submitter
1018722	NM_001572.5(IRF7):c.1001C>T (p.Pro334Leu)	IRF7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021811	NM_001572.5(IRF7):c.1122C>A (p.Cys374Ter)	IRF7	Uncertain significance	criteria provided, single submitter
1023361	NM_001572.5(IRF7):c.1387G>C (p.Glu463Gln)	IRF7	Uncertain significance	criteria provided, single submitter
1025274	NM_001572.5(IRF7):c.398G>A (p.Gly133Asp)	IRF7	Uncertain significance	criteria provided, single submitter
1025304	NM_001572.5(IRF7):c.466G>C (p.Gly156Arg)	IRF7	Uncertain significance	criteria provided, single submitter
1025397	NM_001572.5(IRF7):c.287_293dup (p.Ser101fs)	IRF7	Uncertain significance	criteria provided, single submitter
1036790	NM_001572.5(IRF7):c.434C>T (p.Ala145Val)	IRF7	Uncertain significance	criteria provided, single submitter
1042881	NM_001572.5(IRF7):c.977C>G (p.Pro326Arg)	IRF7	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IRF7	Strong	Autosomal recessive	immunodeficiency 39	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRF7	Orphanet:574918	Predisposition to severe viral infection due to IRF7 deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IRF7	HGNC:6122	ENSG00000185507	Q92985	Interferon regulatory factor 7	gencc,clinvar
LMNTD2	HGNC:28561	ENSG00000185522	Q8IXW0	Lamin tail domain-containing protein 2	clinvar
LSP1	HGNC:6707	ENSG00000130592	P33241	Lymphocyte-specific protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRF7	Interferon regulatory factor 7	Key transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses.
LSP1	Lymphocyte-specific protein 1	May play a role in mediating neutrophil activation and chemotaxis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IRF7	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
LMNTD2	Other/Unknown	no		Lamin_tail_dom, Lamin_tail_dom_sf, Lamin_tail_domain
LSP1	Other/Unknown	no		Lymphspecific, Caldesmon_LSP

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	2
granulocyte	2
right lobe of liver	2
right testis	1
right uterine tube	1
leukocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRF7	134	ubiquitous	marker	granulocyte, blood, right lobe of liver
LMNTD2	129	broad	yes	right uterine tube, right lobe of liver, right testis
LSP1	140	broad	marker	granulocyte, blood, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRF7	3,332
LSP1	1,243
LMNTD2	516

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LSP1	P33241	3
IRF7	Q92985	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMNTD2	Q8IXW0	55.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 3 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
DEx/H-box helicases activate type I IFN and inflammatory cytokines production	1	1631.4×	0.010	IRF7
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling	1	878.5×	0.010	IRF7
TICAM1-dependent activation of IRF3/IRF7	1	815.7×	0.010	IRF7
TRAF3-dependent IRF activation pathway	1	761.3×	0.010	IRF7
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	601.0×	0.010	IRF7
TRAF6 mediated IRF7 activation	1	380.7×	0.012	IRF7
Cytosolic sensors of pathogen-associated DNA	1	285.5×	0.012	IRF7
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	253.8×	0.012	IRF7
Toll Like Receptor 3 (TLR3) Cascade	1	193.6×	0.012	IRF7
TRIF (TICAM1)-mediated TLR4 signaling	1	190.3×	0.012	IRF7
MyD88 dependent cascade initiated on endosome	1	190.3×	0.012	IRF7
MyD88-independent TLR4 cascade	1	184.2×	0.012	IRF7
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	184.2×	0.012	IRF7
Toll Like Receptor 9 (TLR9) Cascade	1	175.7×	0.012	IRF7
Interferon alpha/beta signaling	1	152.3×	0.012	IRF7
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.012	IRF7
Interferon gamma signaling	1	125.5×	0.012	IRF7
Toll-like Receptor Cascades	1	124.1×	0.012	IRF7
Interferon Signaling	1	120.2×	0.012	IRF7
SARS-CoV-2-host interactions	1	119.0×	0.012	IRF7
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.015	IRF7
SARS-CoV-2 Infection	1	80.4×	0.016	IRF7
SARS-CoV Infections	1	55.4×	0.023	IRF7
Cytokine Signaling in Immune system	1	40.8×	0.030	IRF7
Viral Infection Pathways	1	30.8×	0.038	IRF7
Innate Immune System	1	25.5×	0.043	IRF7
Infectious disease	1	24.8×	0.043	IRF7
Disease	1	13.1×	0.077	IRF7
Immune System	1	13.0×	0.077	IRF7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
establishment of viral latency	1	8426.0×	0.002	IRF7
regulation of MyD88-independent toll-like receptor signaling pathway	1	8426.0×	0.002	IRF7
regulation of MyD88-dependent toll-like receptor signaling pathway	1	4213.0×	0.002	IRF7
regulation of monocyte differentiation	1	4213.0×	0.002	IRF7
MDA-5 signaling pathway	1	2106.5×	0.003	IRF7
negative regulation of macrophage apoptotic process	1	1404.3×	0.003	IRF7
regulation of adaptive immune response	1	936.2×	0.004	IRF7
regulation of type I interferon production	1	842.6×	0.004	IRF7
cellular response to interleukin-7	1	648.1×	0.005	LSP1
cytoplasmic pattern recognition receptor signaling pathway	1	443.5×	0.006	IRF7
positive regulation of type I interferon-mediated signaling pathway	1	421.3×	0.006	IRF7
immunoglobulin mediated immune response	1	351.1×	0.007	IRF7
positive regulation of interferon-alpha production	1	324.1×	0.007	IRF7
regulation of immune response	1	247.8×	0.008	IRF7
positive regulation of type I interferon production	1	210.7×	0.009	IRF7
immune system process	1	195.9×	0.009	IRF7
positive regulation of interferon-beta production	1	195.9×	0.009	IRF7
type I interferon-mediated signaling pathway	1	172.0×	0.009	IRF7
cellular defense response	1	159.0×	0.010	LSP1
response to virus	1	72.0×	0.020	IRF7
chemotaxis	1	68.0×	0.020	LSP1
defense response to virus	1	34.7×	0.038	IRF7
DNA damage response	1	26.8×	0.047	IRF7
innate immune response	1	16.8×	0.071	IRF7
positive regulation of DNA-templated transcription	1	14.0×	0.082	IRF7
negative regulation of transcription by RNA polymerase II	1	8.9×	0.122	IRF7
signal transduction	1	8.0×	0.130	LSP1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.135	IRF7
regulation of transcription by RNA polymerase II	1	5.8×	0.164	IRF7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IRF7	0	0
LMNTD2	0	0
LSP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	IRF7, LMNTD2, LSP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IRF7	0	—
LMNTD2	0	—
LSP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.