NMRAL1

Chr 16

NmrA like redox sensor 1

Also known as: HSCARG, SDR48A1

NCBI Gene: 57407 ENSG00000153406 UniProt: Q9HBL8 OMIM: 620004

This gene encodes a redox sensor protein that binds NADPH and regulates cellular responses to changes in NADPH/NADP+ ratios, including modulation of nitric oxide synthesis and interferon signaling pathways. The gene is not highly constrained against loss-of-function variants based on population data (pLI < 0.9, LOEUF > 0.35), suggesting that complete loss of function may be tolerated. No established Mendelian diseases have been definitively associated with NMRAL1 mutations in current medical literature.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes an NADPH sensor protein that preferentially binds to NADPH. The encoded protein also negatively regulates the activity of NF-kappaB in a ubiquitylation-dependent manner. It plays a key role in cellular antiviral response by negatively regulating the interferon response factor 3-mediated expression of interferon beta. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.33

Clinical Summary— NMRAL1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.33LOEUF

pLI 0.000

Z-score 0.76

OE 0.76 (0.46–1.33)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.73Z-score

OE missense 1.15 (1.03–1.29)

216 obs / 187.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.76 (0.46–1.33)

0≤0.351.4

Missense OE?1.15 (1.03–1.29)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 9 / 11.8Missense obs/exp: 216 / 187.7Syn Z: -0.83

This gene — mechanism propensity

0.7131th %ile

GOF

0.6540th %ile

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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