NRROS

Chr 3AR

negative regulator of reactive oxygen species

Also known as: ELLP3030, GARPL1, LRRC33, SENEBAC, UNQ3030

NCBI Gene: 375387 ENSG00000174004 OMIM: 615322

NRROS encodes a key regulator of TGF-beta-1 activation that is specifically required for microglia function in the nervous system, where it associates with latency-associated peptide to enable localized TGF-beta-1 signaling. Biallelic mutations cause autosomal recessive early-onset seizures with neurodegeneration and brain calcification. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.531), consistent with its essential role in microglial regulation of neuroinflammation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables transforming growth factor beta binding activity. Predicted to be involved in several processes, including microglia development; sequestering of TGFbeta in extracellular matrix; and transforming growth factor beta receptor signaling pathway. Located in cell surface. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.531 OMIM phenotype

Clinical Summary— NRROS

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Gene-Disease Validity (ClinGen)

seizures, early-onset, with neurodegeneration and brain calcifications · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 98 VUS of 136 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.326

Z-score 2.96

OE 0.23 (0.11–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.89Z-score

OE missense 0.88 (0.81–0.96)

379 obs / 431.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.11–0.53)

0≤0.351.4

Missense OE?0.88 (0.81–0.96)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 4 / 17.2Missense obs/exp: 379 / 431.1Syn Z: -0.61

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNRROS-related infantile-onset neurodegeneration with intracranial calcificationLOFAR

This gene — mechanism propensity

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

0.6065th %ile

GOF

0.6931th %ile

LOF

0.3648th %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

136 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic5

VUS98

Likely Benign18

Benign5

Conflicting2

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	5	2	0	0	7
Likely Pathogenic	5	0	0	0	5
VUS	0	97	1	0	98
Likely Benign	0	14	0	4	18
Benign	0	2	0	3	5
Conflicting	—				2
Total	10	115	1	7	135

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

View in ClinVar →

88 pathogenic / likely-pathogenic (of 108) ClinVar copy-number / structural variants overlap NRROS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →