hyper-IgM syndrome type 3

Summary

hyper-IgM syndrome type 3 (MONDO:0011735) is a disease caused by CD40 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CD40 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 43

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgM syndrome type 3
Mondo ID	MONDO:0011735
OMIM	606843
Orphanet	101090
DOID	DOID:0060023
UMLS	C1720957
MedGen	328419
GARD	0010579
Is cancer (heuristic)	no

Also known as: CD40 hyper-IgM syndrome · HIGM3 · hyper IgM syndrome 3 · hyper-IgM syndrome caused by mutation in CD40 · hyper-IgM syndrome due to CD40 deficiency · immunodeficiency with hyper IgM type 3 · immunodeficiency with hyper-IgM type 3 · immunodeficiency with hyper-IgM, type 3

Data availability: 43 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgM syndrome › hyper-IgM syndrome type 3

Related subtypes (4): hyper-IgM syndrome type 1, hyper-IgM syndrome type 2, hyper-IgM syndrome type 5, hyper-IgM syndrome type 4

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

43 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 10 benign, 9 conflicting classifications of pathogenicity, 5 pathogenic, 4 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17748	NM_001250.6(CD40):c.408A>T (p.Thr136=)	CD40	Pathogenic	no assertion criteria provided
17749	NM_001250.6(CD40):c.247T>C (p.Cys83Arg)	CD40	Pathogenic	no assertion criteria provided
17750	NM_001250.6(CD40):c.257-2A>T	CD40	Pathogenic	no assertion criteria provided
29611	NM_001250.6(CD40):c.95TAA[1] (p.Ile33del)	CD40	Pathogenic	no assertion criteria provided
4848600	NC_000020.10:g.(?44746952)(44758498_?)del	CD40	Pathogenic	criteria provided, single submitter
3629833	NM_001250.6(CD40):c.430G>A (p.Glu144Lys)	CD40	Likely pathogenic	criteria provided, single submitter
2138350	NM_001250.6(CD40):c.170C>T (p.Thr57Met)	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338571	NM_001250.6(CD40):c.256+8C>T	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338572	NM_001250.6(CD40):c.339T>C (p.Ser113=)	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
439466	NM_001250.6(CD40):c.256+2T>C	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
496127	NM_001250.6(CD40):c.381C>T (p.Pro127=)	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618003	NM_001250.6(CD40):c.750A>G (p.Pro250=)	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
750493	NM_001250.6(CD40):c.444C>T (p.Val148=)	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896159	NM_001250.6(CD40):c.249C>T (p.Cys83=)	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897761	NM_001250.6(CD40):c.498-7T>C	CD40	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338567	NM_001250.4(CD40):c.-55C>G	CD40	Uncertain significance	criteria provided, single submitter
338577	NM_001250.6(CD40):c.*85G>T	CD40	Uncertain significance	criteria provided, single submitter
338580	NM_001250.6(CD40):c.*178G>A	CD40	Uncertain significance	criteria provided, multiple submitters, no conflicts
338582	NM_001250.6(CD40):c.*310C>G	CD40	Uncertain significance	criteria provided, single submitter
338585	NM_001250.6(CD40):c.*547A>T	CD40	Uncertain significance	criteria provided, multiple submitters, no conflicts
338586	NM_001250.6(CD40):c.*677G>A	CD40	Uncertain significance	criteria provided, single submitter
895885	NM_001250.4(CD40):c.-67G>T	CD40	Uncertain significance	criteria provided, single submitter
895948	NM_001250.6(CD40):c.*372A>C	CD40	Uncertain significance	criteria provided, single submitter
895949	NM_001250.6(CD40):c.*560C>T	CD40	Uncertain significance	criteria provided, single submitter
895950	NM_001250.6(CD40):c.*676C>T	CD40	Uncertain significance	criteria provided, single submitter
897759	NM_001250.6(CD40):c.311C>T (p.Thr104Ile)	CD40	Uncertain significance	criteria provided, single submitter
897760	NM_001250.6(CD40):c.379C>T (p.Pro127Ser)	CD40	Uncertain significance	criteria provided, single submitter
898906	NM_001250.6(CD40):c.622A>G (p.Ile208Val)	CD40	Uncertain significance	criteria provided, multiple submitters, no conflicts
338566	NM_001250.4(CD40):c.-61G>T	LOC127893450	Uncertain significance	criteria provided, single submitter
2428741	NM_001250.6(CD40):c.646+27G>T	CD40	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CD40	Definitive	Autosomal recessive	hyper-IgM syndrome type 3	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD40	Orphanet:101090	Hyper-IgM syndrome type 3

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
CD40	HGNC:11919	ENSG00000101017	P25942	Tumor necrosis factor receptor superfamily member 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD40	Tumor necrosis factor receptor superfamily member 5	Receptor for TNFSF5/CD40LG.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD40	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_5, TNFRSF5_N

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
lymph node	1
right lung	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD40	242	ubiquitous	marker	lymph node, right lung, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD40	3,765

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD40	P25942	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	671.8×	0.004	CD40
TNFR2 non-canonical NF-kB pathway	1	181.3×	0.008	CD40
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.011	CD40

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
response to cobalamin	1	8426.0×	0.001	CD40
positive regulation of protein kinase C signaling	1	5617.3×	0.001	CD40
positive regulation of interleukin-4-mediated signaling pathway	1	5617.3×	0.001	CD40
B cell mediated immunity	1	4213.0×	0.001	CD40
cellular response to erythropoietin	1	4213.0×	0.001	CD40
immune response-regulating cell surface receptor signaling pathway	1	1872.4×	0.003	CD40
CD40 signaling pathway	1	1685.2×	0.003	CD40
positive regulation of isotype switching to IgG isotypes	1	1532.0×	0.003	CD40
positive regulation of endothelial cell apoptotic process	1	732.7×	0.005	CD40
defense response to protozoan	1	601.9×	0.005	CD40
response to type II interferon	1	526.6×	0.005	CD40
B cell proliferation	1	481.5×	0.005	CD40
B cell activation	1	455.5×	0.005	CD40
positive regulation of interleukin-12 production	1	391.9×	0.005	CD40
positive regulation of blood vessel endothelial cell migration	1	391.9×	0.005	CD40
positive regulation of B cell proliferation	1	343.9×	0.006	CD40
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.006	CD40
cellular response to interleukin-1	1	280.9×	0.006	CD40
platelet activation	1	267.5×	0.006	CD40
cellular response to mechanical stimulus	1	216.1×	0.007	CD40
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	CD40
cellular response to tumor necrosis factor	1	163.6×	0.009	CD40
intracellular calcium ion homeostasis	1	145.3×	0.009	CD40
positive regulation of angiogenesis	1	115.4×	0.011	CD40
protein-containing complex assembly	1	113.9×	0.011	CD40
cellular response to lipopolysaccharide	1	98.0×	0.012	CD40
positive regulation of MAPK cascade	1	80.6×	0.014	CD40
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.015	CD40
defense response to virus	1	69.3×	0.015	CD40
inflammatory response	1	37.7×	0.027	CD40

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
CD40	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
CD40	10	Binding:10

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	CD40

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)
CD40	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.