NAPRT

Chr 8

nicotinate phosphoribosyltransferase

ENSG00000147813 UniProt: Q6XQN6 OMIM: 611552

Nicotinic acid phosphoribosyltransferase catalyzes the first step in NAD biosynthesis from nicotinic acid, converting nicotinic acid and 5-phospho-D-ribose 1-phosphate to beta-nicotinate D-ribonucleotide in an ATP-dependent reaction. Biallelic mutations cause pellagra-like dermatitis with neurologic and psychiatric manifestations, inherited in an autosomal recessive pattern. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern of associated disease.

OMIM ResearchSummary from RefSeq, UniProt

Catalyzes the first step in the biosynthesis of NAD from nicotinic acid, the ATP-dependent synthesis of beta-nicotinate D-ribonucleotide from nicotinate and 5-phospho-D-ribose 1-phosphate (PubMed:17604275, PubMed:21742010, PubMed:26042198). Helps prevent cellular oxidative stress via its role in NAD biosynthesis (PubMed:17604275)

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.43

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.000

Z-score -0.16

OE 1.03 (0.76–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.62Z-score

OE missense 1.10 (1.00–1.21)

331 obs / 300.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.03 (0.76–1.43)

0≤0.351.4

Missense OE?1.10 (1.00–1.21)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 27 / 26.1Missense obs/exp: 331 / 300.9Syn Z: -1.21

Background carrier burden — how many people carry a rare variant somewhere in NAPRT?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 54

891 rare PASS variants

Rare truncating (LoF)

1 in 400

192 rare PASS variants

Rare synonymous (reference)

1 in 92

425 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NAPRT. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 69	1 in 390
South Asian	~43k	1 in 46	1 in 290
Remaining (unassigned)	~30k	1 in 43	1 in 690
European (Finnish)	~26k	1 in 200	1 in 3,200
Admixed American	~22k	1 in 46	1 in 370
African / African American	~21k	1 in 48	1 in 380
East Asian	~20k	1 in 59	1 in 820
Ashkenazi Jewish	~13k	1 in 220	1 in 1,400
Middle Eastern	~2,884	1 in 62	1 in 410

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 13 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 13.? see exons ↓