GeneBe

NMNAT1

protein-coding

nicotinamide nucleotide adenylyltransferase 1, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD). The encoded enzyme is one of several nicotinamide nucleotide adenylyltransferases, and is specifically localized to the cell nucleus. Activity of this protein leads to the activation of a nuclear deacetylase that functions in the protection of damaged neurons. Mutations in this gene have been associated with Leber congenital amaurosis 9. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are located on chromosomes 1, 3, 4, 14, and 15. [provided by RefSeq, Jul 2014]

Previous symbols:
  • LCA9

MANE transcript

NM_022787.4

Inheritance

AR, AD

ClinVar variants

P:69U:86B:45

Top phenotype

Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr1:9,943,428-9,985,501

External References & Databases

Ensembl (ENSG00000173614)NCBI Gene (64802)OMIM (608700)HGNC:17877GenCCUniProt (Q9HAN9)AlphaFoldClinVar (NMNAT1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~42.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leber congenital amaurosis 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012056

Submitter: G2P

Leber congenital amaurosis 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012056

Submitter: Labcorp Genetics (formerly Invitae)

NMNAT1-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800101

Submitter: ClinGen

NMNAT1 was first reported in relation to NMNAT1-related retinopathy in 2012 in a patient described as having autosomal recessive Leber congenital amaurosis (PMID: 22842230, 22842231, 22842227). Leber congenital amaurosis (LCA) is a severe form of inherited photoreceptor-neuron degeneration resulting in congenital blindness. To take into account the range of phenotypes and genetic heterogeneity in retinal disorders, the ClinGen Retina GCEP has labeled the disease entity associated with biallelic variants in NMNAT1 as "NMNAT1-related retinopathy". At least 14 variants (missense and nonsense) that have been reported in 15 probands in publications (PMID: 22842230, 22842231, 22842227, 32150116). Variants in NMNAT1 was found to be segregated in at least one large family (PMID: 22842230).More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by in-vitro studies (e.g. animal models, expression studies, in vitro functional assays, etc.) (PMIDs: 22842230, 22842227). When measuring NAD levels in red blood cells, affected individuals with homozygous NMNAT1 variant had significantly lower levels of NAD compared to unaffected carrier (PMID: 22842230). Other in-vitro studies showed that, when cells are transfected with constructs encoding wild-type or mutant NMNAT1, those with NMNAT1 variants had lower enzymatic activities, compared to wildtype (PMID: 22842230, 22842227). Of note, one study demonstrated that patients with two homozygous variants in NMNAT in a large consanguineous family presented with global developmental delay, hypotonia with joint hypermobility and autism, in addition to LCA (PMID: 22842227). A limited number of patients have been recorded as having spondyloepiphyseal dysplasia syndrome (SHILCA), including sensorineural hearing loss, intellectual disability in addition to LCA, however additional studies are needed to definitively describe this disease association (PMID: 33668384, 32533184). In summary, NMNAT1 is definitively associated with autosomal recessive NMNAT1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0031007

Submitter: Labcorp Genetics (formerly Invitae)

Leber congenital amaurosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

NMNAT1-related retinopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800101

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosisAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Among other findings, the condition can include sensorineural hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 22842227; 22842229; 22842230; 22842231; 32533184; 33668384Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NMNAT1 variants in ClinVar

22 Conditions Cataloged
Leber congenital amaurosis 9Total: 187
not providedTotal: 47
NMNAT1-related disorderTotal: 41
Inborn genetic diseasesTotal: 25
not specifiedTotal: 23
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosisTotal: 12
Leber congenital amaurosisTotal: 6
Retinal dystrophyTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022787.4. 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
40
clinvar
 41
missense
8
clinvar
40
clinvar
78
clinvar
5
clinvar
 131
nonsense
8
clinvar
2
clinvar
 10
start loss
1
clinvar
 1
frameshift
5
clinvar
3
clinvar
1
clinvar
 9
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
4
clinvar
 8
Total234686450200

Highest pathogenic variant AF is 0.0010092024

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_022787.4RefSeqNP_073624.24MANE Select
ENST00000377205.6EnsemblENSP00000366410.14MANE Select
NM_001297778.1RefSeqNP_001284707.14Standard
NM_001297779.2RefSeqNP_001284708.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Nicotinate and nicotinamide metabolism - Homo sapiens (human)
  • NAD Biosynthesis II (from tryptophan)
  • NAD+ metabolism
  • NAD+ biosynthetic pathways
  • Vitamin B3 (nicotinate and nicotinamide) metabolism

Biological Process

  • NAD biosynthetic process
  • response to wounding
  • NAD metabolic process
  • 'de novo' NAD biosynthetic process from aspartate
  • positive regulation of MAPK cascade

Molecular Function

  • nicotinamide-nucleotide adenylyltransferase activity
  • nicotinate-nucleotide adenylyltransferase activity
  • protein binding
  • ATP binding
  • identical protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • nuclear body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000377205
Coding exons
4
Length
42074
Individuals with no LoFs
125728
Homozygous LoFs
0
Heterozygous LoFs
19
Defined
125747
p
0.0000756
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6271291510.8560.000007641838
Missense (PolyPhen)5259.9390.86755729
Synonymous0.6395056.10.8910.00000282524
Loss of Function1.85410.40.3834.39e-7138

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian0.0000560.000054rare
Finnish00.0absent
European (Non-Finnish)0.000120.00012rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP (PubMed:17402747). Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate with the same efficiency (PubMed:17402747). Can use triazofurin monophosphate (TrMP) as substrate (PubMed:17402747). Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+) (PubMed:17402747). For the pyrophosphorolytic activity, prefers NAD(+) and NaAD as substrates and degrades NADH, nicotinic acid adenine dinucleotide phosphate (NHD) and nicotinamide guanine dinucleotide (NGD) less effectively (PubMed:17402747). Involved in the synthesis of ATP in the nucleus, together with PARP1, PARG and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257). Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+) (PubMed:17402747). Protects against axonal degeneration following mechanical or toxic insults (By similarity). {ECO:0000250|UniProtKB:Q9EPA7, ECO:0000269|PubMed:17402747, ECO:0000269|PubMed:27257257}.;

Intolerance Scores

LoFtool
0.300
RVIS EVS
0.15
RVIS percentile EVS
64.32

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.676

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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