hyper-IgM syndrome type 5

Summary

hyper-IgM syndrome type 5 (MONDO:0011971) is a disease caused by UNG (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: UNG (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 277

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgM syndrome type 5
Mondo ID	MONDO:0011971
OMIM	608106
Orphanet	101092
DOID	DOID:0060759
UMLS	C1720958
MedGen	328420
GARD	0010581
Is cancer (heuristic)	no

Also known as: HIGM5 · hyper IgM syndrome 5 · hyper-IgM syndrome 5 · hyper-IgM syndrome caused by mutation in UNG · hyper-IgM syndrome due to UNG deficiency · hyper-IgM syndrome due to uracil N-glycosylase · hyper-IgM syndrome type 5 · immunodeficiency with hyper IgM, type 5 · immunodeficiency with hyper-IgM, type 5 · UNG hyper-IgM syndrome

Data availability: 277 ClinVar variants · 4 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 5

Related subtypes (4): hyper-IgM syndrome type 1, hyper-IgM syndrome type 2, hyper-IgM syndrome type 3, 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

277 retrieved; paginated sample, class counts are floors:

126 uncertain significance, 108 likely benign, 15 pathogenic, 12 conflicting classifications of pathogenicity, 8 benign, 7 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064649	NM_080911.3(UNG):c.294del (p.Ser97_Trp98insTer)	UNG	Pathogenic	criteria provided, single submitter
1074636	NM_080911.3(UNG):c.730C>T (p.Gln244Ter)	UNG	Pathogenic	criteria provided, single submitter
12290	NM_080911.3(UNG):c.392del (p.Pro131fs)	UNG	Pathogenic	criteria provided, single submitter
12291	NM_080911.3(UNG):c.572_573del (p.Glu191fs)	UNG	Pathogenic	no assertion criteria provided
12292	NM_080911.3(UNG):c.752T>C (p.Phe251Ser)	UNG	Pathogenic	no assertion criteria provided
12293	NM_080911.3(UNG):c.428_429del (p.Ile143fs)	UNG	Pathogenic	no assertion criteria provided
1452551	NM_080911.3(UNG):c.366_369del (p.Arg122fs)	UNG	Pathogenic	criteria provided, single submitter
1687471	NM_080911.3(UNG):c.649dup (p.Thr217fs)	UNG	Pathogenic	criteria provided, single submitter
2048165	NM_080911.3(UNG):c.250dup (p.Arg84fs)	UNG	Pathogenic	criteria provided, single submitter
2068429	NM_080911.3(UNG):c.162del (p.Gln55fs)	UNG	Pathogenic	criteria provided, single submitter
2083377	NM_080911.3(UNG):c.39del (p.Ser14fs)	UNG	Pathogenic	criteria provided, single submitter
2735958	NM_080911.3(UNG):c.569_570del (p.Ile190fs)	UNG	Pathogenic	criteria provided, single submitter
3650570	NM_080911.3(UNG):c.682del (p.Glu228fs)	UNG	Pathogenic	criteria provided, single submitter
3653806	NM_080911.3(UNG):c.348del (p.Phe117fs)	UNG	Pathogenic	criteria provided, single submitter
578381	NM_080911.3(UNG):c.685C>T (p.Arg229Ter)	UNG	Pathogenic	criteria provided, single submitter
2725894	NM_080911.3(UNG):c.132+1G>A	LOC130008712	Likely pathogenic	criteria provided, single submitter
1508776	NM_080911.3(UNG):c.623-2A>G	UNG	Likely pathogenic	criteria provided, single submitter
2787212	NM_080911.3(UNG):c.133-2A>G	UNG	Likely pathogenic	criteria provided, single submitter
3574190	NM_080911.3(UNG):c.294G>A (p.Trp98Ter)	UNG	Likely pathogenic	criteria provided, single submitter
3574191	NM_080911.3(UNG):c.454G>T (p.Gly152Ter)	UNG	Likely pathogenic	criteria provided, single submitter
3574192	NM_080911.3(UNG):c.551_552del (p.Lys184fs)	UNG	Likely pathogenic	criteria provided, single submitter
4751175	NM_080911.3(UNG):c.533+1G>T	UNG	Likely pathogenic	criteria provided, single submitter
306966	NM_080911.3(UNG):c.81C>A (p.Ala27=)	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
306968	NM_080911.3(UNG):c.204C>G (p.Ala68=)	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
306971	NM_080911.3(UNG):c.435+15T>A	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
306973	NM_080911.3(UNG):c.533+6G>A	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
306976	NM_080911.3(UNG):c.660C>T (p.Ala220=)	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3363490	NM_080911.3(UNG):c.313G>T (p.Glu105Ter)	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36894	NM_080911.3(UNG):c.246G>C (p.Leu82=)	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440391	NM_080911.3(UNG):c.262C>T (p.Arg88Cys)	UNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
UNG	Strong	Autosomal recessive	hyper-IgM syndrome type 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UNG	Orphanet:101092	Hyper-IgM syndrome type 5

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UNG	HGNC:12572	ENSG00000076248	P13051	Uracil-DNA glycosylase	gencc,clinvar
ACACB	HGNC:85	ENSG00000076555	O00763	Acetyl-CoA carboxylase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UNG	Uracil-DNA glycosylase	Uracil-DNA glycosylase that hydrolyzes the N-glycosidic bond between uracil and deoxyribose in single- and double-stranded DNA (ssDNA and dsDNA) to release a free uracil residue and form an abasic (apurinic/apyrimidinic; AP) site.
ACACB	Acetyl-CoA carboxylase 2	Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UNG	Enzyme (other)	yes	3.2.2.27	UDG_fam1, Uracil-DNA_glycosylase-like, Ura-DNA_Glyclase_AS
ACACB	Enzyme (other)	yes	6.3.4.14	Biotin_lipoyl, CPAse_ATP-bd, BC-like_N

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
right adrenal gland cortex	1
secondary oocyte	1
adipose tissue	1
subcutaneous adipose tissue	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UNG	293	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland cortex
ACACB	288	ubiquitous	marker	tendon of biceps brachii, adipose tissue, subcutaneous adipose tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACACB	2,991
UNG	1,702

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UNG	P13051	24
ACACB	O00763	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ChREBP activates metabolic gene expression	1	634.4×	0.010	ACACB
Displacement of DNA glycosylase by APEX1	1	519.1×	0.010	UNG
Biotin transport and metabolism	1	519.1×	0.010	ACACB
Carnitine shuttle	1	380.7×	0.011	ACACB
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.018	ACACB
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.018	ACACB
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.018	UNG
Cleavage of the damaged pyrimidine	1	92.1×	0.018	UNG
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.018	ACACB
Integration of energy metabolism	1	87.8×	0.018	ACACB
Chromatin modifications during the maternal to zygotic transition (MZT)	1	81.6×	0.018	UNG
Metabolism of steroids	1	68.8×	0.019	ACACB
Fatty acid metabolism	1	65.6×	0.019	ACACB
Metabolism of vitamins and cofactors	1	58.3×	0.020	ACACB
Metabolism of lipids	1	15.8×	0.067	ACACB
Metabolism	1	5.8×	0.165	ACACB

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
lactic acid secretion	1	8426.0×	0.001	ACACB
intracellular aspartate homeostasis	1	8426.0×	0.001	ACACB
base-excision repair, AP site formation via deaminated base removal	1	8426.0×	0.001	UNG
regulation of cardiac muscle hypertrophy in response to stress	1	4213.0×	0.001	ACACB
malonyl-CoA biosynthetic process	1	4213.0×	0.001	ACACB
negative regulation of fatty acid beta-oxidation	1	2106.5×	0.002	ACACB
positive regulation of heart growth	1	2106.5×	0.002	ACACB
tricarboxylic acid metabolic process	1	1404.3×	0.002	ACACB
intracellular glutamate homeostasis	1	1404.3×	0.002	ACACB
acetyl-CoA metabolic process	1	1203.7×	0.002	ACACB
depyrimidination	1	936.2×	0.003	UNG
pentose-phosphate shunt	1	766.0×	0.003	ACACB
response to caloric restriction	1	766.0×	0.003	ACACB
single strand break repair	1	702.2×	0.003	UNG
positive regulation of lipid storage	1	702.2×	0.003	ACACB
somatic hypermutation of immunoglobulin genes	1	526.6×	0.003	UNG
fatty acid oxidation	1	526.6×	0.003	ACACB
fatty acid homeostasis	1	468.1×	0.003	ACACB
isotype switching	1	421.3×	0.003	UNG
obsolete D-glucose import	1	421.3×	0.003	ACACB
regulation of glucose metabolic process	1	280.9×	0.005	ACACB
base-excision repair	1	234.1×	0.005	UNG
fatty acid biosynthetic process	1	175.5×	0.007	ACACB
response to nutrient	1	147.8×	0.008	ACACB
energy homeostasis	1	135.9×	0.008	ACACB
protein homotetramerization	1	118.7×	0.009	ACACB
response to xenobiotic stimulus	1	34.5×	0.030	ACACB
negative regulation of apoptotic process	1	17.4×	0.057	UNG

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ACACB	BEMPEDOIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACACB	4	4
UNG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEMPEDOIC ACID	4	ACACB
PF-05175157	2	ACACB
FIRSOCOSTAT	2	ACACB
CLESACOSTAT	2	ACACB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ACACB	81	Binding:81
UNG	7	Binding:6, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UNG	3.2.2.27	uracil-DNA glycosylase
ACACB	6.3.4.14, 6.4.1.2	biotin carboxylase, acetyl-CoA carboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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.

Compound	Max phase	Cohort target (bioactivity)
BEMPEDOIC ACID	4	ACACB
PF-05175157	2	ACACB
FIRSOCOSTAT	2	ACACB
CLESACOSTAT	2	ACACB

Druggability pyramid

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

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

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)
UNG	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.