NMNAT1

Chr 1AR

nicotinamide nucleotide adenylyltransferase 1

Also known as: LCA9, NMNAT, PNAT1, SHILCA

NCBI Gene: 64802 ENSG00000173614 UniProt: Q9HAN9 OMIM: 608700

This nuclear enzyme catalyzes the formation of NAD+ from nicotinamide mononucleotide and ATP, playing a critical role in nuclear energy metabolism and neuroprotection against axonal degeneration. Mutations cause Leber congenital amaurosis 9 (severe early-onset retinal dystrophy leading to blindness in infancy) and a multisystem disorder involving spondyloepiphyseal dysplasia, sensorineural hearing loss, and intellectual disability. Inheritance is autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.882 OMIM phenotypes

Clinical Summary— NMNAT1

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Gene-Disease Validity (ClinGen)

NMNAT1-related retinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

79 unique Pathogenic / Likely Pathogenic· 84 VUS of 239 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NMNAT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.035

Z-score 1.85

OE 0.38 (0.19–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.63Z-score

OE missense 0.86 (0.74–0.99)

129 obs / 150.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.19–0.88)

0≤0.351.4

Missense OE?0.86 (0.74–0.99)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 4 / 10.4Missense obs/exp: 129 / 150.6Syn Z: 0.64

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNMNAT1-related Leber congenital amaurosisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.74top 25%

GOF

0.5856th %ile

LOF

0.2678th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

239 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40

Likely Pathogenic39

VUS84

Likely Benign60

Benign2

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	10	13	0	40
Likely Pathogenic	4	29	6	0	39
VUS	3	74	7	0	84
Likely Benign	0	2	20	38	60
Benign	0	0	2	0	2
Conflicting	—				9
Total	24	115	48	38	234

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

34 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap NMNAT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →