Glucocorticoid deficiency 4

Summary

Glucocorticoid deficiency 4 (MONDO:0013874) is a disease caused by NNT (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NNT (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glucocorticoid deficiency 4
Mondo ID	MONDO:0013874
OMIM	614736
DOID	DOID:0061243
NCIT	C131452
UMLS	C3553587
MedGen	766501
GARD	0015840
Is cancer (heuristic)	no

Also known as: familial glucocorticoid deficiency caused by mutation in NNT · GCCD4 · glucocorticoid deficiency 4 · glucocorticoid deficiency 4, with or without mineralocorticoid deficiency · glucocorticoid deficiency type 4 · NNT familial glucocorticoid deficiency

Data availability: 34 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial glucocorticoid deficiency › glucocorticoid deficiency 4

Related subtypes (5): adrenocortical unresponsiveness to ACTH with postreceptor defect, glucocorticoid deficiency 2, glucocorticoid deficiency 3, glucocorticoid deficiency 1, glucocorticoid deficiency 5

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

34 retrieved; paginated sample, class counts are floors:

15 pathogenic, 8 uncertain significance, 5 benign, 5 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1119993	NM_182977.3(NNT):c.2274del (p.Ile758fs)	NNT	Pathogenic	no assertion criteria provided
1705295	NM_182977.3(NNT):c.1089del (p.Leu362_Tyr363insTer)	NNT	Pathogenic	criteria provided, single submitter
1705519	NM_182977.3(NNT):c.2635-1G>T	NNT	Pathogenic	criteria provided, single submitter
2112825	NM_182977.3(NNT):c.1356_1357del (p.Lys453fs)	NNT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218365	NM_182977.3(NNT):c.1259dup (p.His421fs)	NNT	Pathogenic	criteria provided, single submitter
265839	NM_182977.3(NNT):c.644T>C (p.Phe215Ser)	NNT	Pathogenic	no assertion criteria provided
265843	NM_182977.3(NNT):c.385C>T (p.Arg129Ter)	NNT	Pathogenic	no assertion criteria provided
265844	NM_182977.3(NNT):c.211C>T (p.Arg71Ter)	NNT	Pathogenic	criteria provided, single submitter
2686048	NM_182977.3(NNT):c.1025T>C (p.Val342Ala)	NNT	Pathogenic	criteria provided, single submitter
35538	NM_182977.3(NNT):c.1598C>T (p.Ala533Val)	NNT	Pathogenic	no assertion criteria provided
35539	NM_182977.3(NNT):c.600-1del	NNT	Pathogenic	no assertion criteria provided
35540	NM_182977.3(NNT):c.2930T>C (p.Leu977Pro)	NNT	Pathogenic	no assertion criteria provided
35541	NM_182977.3(NNT):c.1107_1110del (p.Thr369_His370insTer)	NNT	Pathogenic	no assertion criteria provided
35542	NM_182977.3(NNT):c.3027T>G (p.Asn1009Lys)	NNT	Pathogenic	no assertion criteria provided
35543	NM_182977.3(NNT):c.3022G>C (p.Ala1008Pro)	NNT	Pathogenic	no assertion criteria provided
800942	NM_182977.3(NNT):c.98dup (p.Leu33fs)	NNT	Pathogenic	criteria provided, single submitter
265842	NM_182977.3(NNT):c.598G>A (p.Gly200Ser)	NNT	Likely pathogenic	criteria provided, single submitter
3767966	NM_182977.3(NNT):c.2519_2522dup (p.Tyr841Ter)	NNT	Likely pathogenic	criteria provided, single submitter
4819794	NM_182977.3(NNT):c.1820dup (p.Gly608fs)	NNT	Likely pathogenic	criteria provided, single submitter
4819930	NM_182977.3(NNT):c.1861C>T (p.Gln621Ter)	NNT	Likely pathogenic	criteria provided, single submitter
930557	NM_182977.3(NNT):c.1575dup (p.Pro526fs)	NNT	Likely pathogenic	criteria provided, single submitter
1030250	NM_182977.3(NNT):c.1424C>T (p.Thr475Met)	NNT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030251	NM_182977.3(NNT):c.1817T>C (p.Val606Ala)	NNT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030252	NM_182977.3(NNT):c.1880C>T (p.Ser627Leu)	NNT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030253	NM_182977.3(NNT):c.2778C>A (p.Ser926Arg)	NNT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1475294	NM_182977.3(NNT):c.1765A>T (p.Thr589Ser)	NNT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1687180	NM_182977.3(NNT):c.1822G>A (p.Gly608Arg)	NNT	Uncertain significance	criteria provided, single submitter
3592692	NM_182977.3(NNT):c.1765A>G (p.Thr589Ala)	NNT	Uncertain significance	criteria provided, single submitter
3731368	NM_182977.3(NNT):c.922T>C (p.Cys308Arg)	NNT	Uncertain significance	criteria provided, single submitter
1174913	NM_182977.3(NNT):c.46C>T (p.Leu16=)	NNT	Benign	criteria provided, multiple submitters, no conflicts

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
NNT	Definitive	Autosomal recessive	glucocorticoid deficiency 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NNT	Orphanet:361	Familial glucocorticoid deficiency

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
NNT	HGNC:7863	ENSG00000112992	Q13423	NAD(P) transhydrogenase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NNT	NAD(P) transhydrogenase, mitochondrial	The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NNT	Enzyme (other)	yes	1.6.1.2	AlaDH/PNT_NAD(H)-bd, AlaDH/PNT_N, AlaDH/PNT_CS1

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
biceps brachii	1
heart right ventricle	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NNT	284	ubiquitous	marker	heart right ventricle, hindlimb stylopod muscle, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NNT	1,925

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NNT	Q13423	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Citric acid cycle (TCA cycle)	1	423.0×	0.002	NNT

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 vitamin	1	8426.0×	7e-04	NNT
positive regulation of hydrogen peroxide catabolic process	1	8426.0×	7e-04	NNT
NADPH regeneration	1	3370.4×	0.001	NNT
positive regulation of mitochondrial membrane potential	1	2106.5×	0.001	NNT
cellular oxidant detoxification	1	1872.4×	0.001	NNT
intracellular oxygen homeostasis	1	1532.0×	0.001	NNT
tricarboxylic acid cycle	1	510.7×	0.003	NNT
reactive oxygen species metabolic process	1	468.1×	0.003	NNT
cell redox homeostasis	1	343.9×	0.004	NNT
proton transmembrane transport	1	312.1×	0.004	NNT
negative regulation of apoptotic process	1	34.8×	0.029	NNT

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
NNT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NNT	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NNT	1.6.1.2, 7.1.1.1	NAD(P)+ transhydrogenase (Re/Si-specific), proton-translocating NAD(P)+ transhydrogenase

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	1	NNT
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)
NNT	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.