GeneBe

NNT

protein-coding

nicotinamide nucleotide transhydrogenase

Gene summary

This gene encodes an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis and in free radical detoxification. [provided by RefSeq, Sep 2016]

MANE transcript

NM_182977.3

Inheritance

AR

ClinVar variants

P:36U:164B:77

Top phenotype

Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr5:43,602,692-43,707,405

External References & Databases

Ensembl (ENSG00000112992)NCBI Gene (23530)OMIM (607878)HGNC:7863GenCCUniProt (Q13423)AlphaFoldClinVar (NNT)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~104.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glucocorticoid deficiency 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013874

Submitter: Labcorp Genetics (formerly Invitae)

glucocorticoid deficiency 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013874

Submitter: PanelApp Australia

familial glucocorticoid deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008733

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NNT* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 15, 2024. The *NNT* gene encodes nicotinamide nucleotide transhydrogenase, a pyridine nucleotide transhydrogenase found in the inner mitochondrial membrane, and catalyzes the transfer of hydride ions between NAD(H) and NADP(H). *NNT* was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22634753). While various names have been given to the constellation of features seen in those with *NNT*-related disorders, including glucocorticoid deficiency, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NNT phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine variants (three missense, six nonsense or frameshift), in ten cases from ten publications (PMIDs: 22634753, 26070314, 26548497, 25459914, 38261461, 27129361, 35627102, 36478070, 26523528, 37352919). Clinical features in affected individuals include glucocorticoid deficiency, ptosis, hypertrophic cardiomyopathy, epilepsy and hypoglycemic seizures, developmental delay, and cardiac arrest. The mechanism of disease is loss of function. This gene-disease association is also supported by its expression in adrenal tissue, and skeletal muscle, liver tissue, and heart, and functional alteration and rescue in non-patient cells (PMIDs: 34321199, 22634753, 36478070). Of note, there is a mouse model of this disorder showing phenotypic overlap with glucocorticoid deficiency (PMIDs: 23747984, 29046340) and a congenic mouse model shows an age-dependent effect on skeletal muscle in mice with Nnt knockout (PMID: 38795789). Evidence regarding cardiomyopathy in Nnt knockout mice is contested (PMID: 32213617) and therefore mouse cardiomyopathy phenotypes were not included in this curation. In summary, there is definitive evidence to support the relationship between *NNT* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 15, 2024 (SOP Version 10).

glucocorticoid deficiency 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013874

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Glucocorticoid deficiency 4, with or without mineralocorticoid deficiencyAR

Manifestation: Cardiovascular; Endocrine

Intervention: Cardiovascular; Endocrine

Rationale: The condition can involve early-onset life-threatening sequelae of glucocorticoid deficiency as well as later effects involving mineralocorticoid deficiency and other manifestations (eg, possible thyroid and cardiac findings) and awareness may allow preventive/treatment measures (eg, with corticosteroid replacement therapy) related to adrenal insufficiency

Refs: 22634753; 23474776; 25879317; 26070314; 27129361Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NNT variants in ClinVar

7 Conditions Cataloged
not providedTotal: 167
Inborn genetic diseasesTotal: 120
NNT-related disorderTotal: 35
Glucocorticoid deficiency 4Total: 32
not specifiedTotal: 10
GLUCOCORTICOID DEFICIENCY 4 WITH MINERALOCORTICOID DEFICIENCYTotal: 2
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182977.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
58
clinvar
6
clinvar
 65
missense
6
clinvar
5
clinvar
157
clinvar
10
clinvar
3
clinvar
 181
nonsense
3
clinvar
2
clinvar
 5
start loss
0
frameshift
7
clinvar
7
clinvar
 14
splice donor/acceptor (+/-2bp)
3
clinvar
3
clinvar
6
clinvar
 12
Total1917164689277

Highest pathogenic variant AF is 0.000009109058

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_182977.3RefSeqNP_892022.221MANE Select
ENST00000344920.9EnsemblENSP00000343873.421MANE Select
NM_001331026.2RefSeqNP_001317955.119Standard
NM_012343.4RefSeqNP_036475.321Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Nicotinate and nicotinamide metabolism - Homo sapiens (human)
  • Nicotinate and Nicotinamide Metabolism
  • Citric acid cycle (TCA cycle)
  • Pyruvate metabolism and Citric Acid (TCA) cycle
  • The citric acid (TCA) cycle and respiratory electron transport

Biological Process

  • negative regulation of protein phosphorylation
  • tricarboxylic acid cycle
  • NADPH regeneration
  • positive regulation of mitochondrial membrane potential
  • oxygen homeostasis

Molecular Function

  • NAD(P)+ transhydrogenase (B-specific) activity
  • NAD(P)+ transhydrogenase activity
  • NADP binding
  • NAD binding

Cellular Component

  • mitochondrion
  • mitochondrial inner membrane
  • mitochondrial respirasome
  • membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264663
Coding exons
21
Length
104714
Individuals with no LoFs
125727
Homozygous LoFs
0
Heterozygous LoFs
21
Defined
125748
p
0.0000835
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.084485910.7590.00002986969
Missense (PolyPhen)174272.410.638743166
Synonymous0.4802172260.9590.00001262302
Loss of Function5.22846.40.1720.00000253576

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.0000950.000087rare
Ashkenazi Jewish0.000200.000099rare
East Asian0.000110.00011rare
Finnish0.0000930.000092rare
European (Non-Finnish)0.0000720.000070rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane. May play a role in reactive oxygen species (ROS) detoxification in the adrenal gland. {ECO:0000269|PubMed:22634753}.;

Recessive Scores

pRec
0.0918

Intolerance Scores

LoFtool
0.0186
RVIS EVS
-0.39
RVIS percentile EVS
27.03

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.996

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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