NRROS

protein-coding

negative regulator of reactive oxygen species

Gene summary

Enables transforming growth factor beta binding activity. Predicted to be involved in several processes, including microglia development; obsolete sequestering of TGFbeta in extracellular matrix; and transforming growth factor beta receptor signaling pathway. Located in cell surface. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

LRRC33

MANE transcript

NM_198565.3

Inheritance

ClinVar variants

P:12U:99B:25

Top phenotype

Seizures, early-onset, with neurodegeneration and brain calcification

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr3:196,639,694-196,662,004

External References & Databases

Ensembl (ENSG00000174004)

Transcript & Mutation Effects

hg38 • Region Span ~22.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

seizures, early-onset, with neurodegeneration and brain calcificationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030033

Submitter: Labcorp Genetics (formerly Invitae)

seizures, early-onset, with neurodegeneration and brain calcificationsMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030033

Submitter: Ambry Genetics

seizures, early-onset, with neurodegeneration and brain calcificationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030033

Submitter: PanelApp Australia

seizures, early-onset, with neurodegeneration and brain calcificationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030033

Submitter: Illumina

seizures, early-onset, with neurodegeneration and brain calcificationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030033

Submitter: G2P

seizures, early-onset, with neurodegeneration and brain calcificationsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030033

Submitter: ClinGen

The NRROS gene is located on chromosome 3 at 3q29 and encodes the negative regulator of reactive oxygen species (NRROS) protein, a leucine-rich repeat domain containing transmembrane protein that localizes to the endoplasmic reticulum and plasma membrane. The protein is preferentially expressed in the myeloid cells, microglia and periventricular macrophages of the brain and plays a role in the activation of the TGF-beta-1 signaling pathway and other proteins associated with innate immunity. The NRROS gene was first reported in relation to autosomal recessive early onset seizures with neurodegeneration and brain calcification in 2020 (Smith et al., PMID: 32100099). The clinical course is characterized by normal development to moderate global developmental delay during the first months of life, followed by the onset of seizures and then rapid, severe, progressive developmental regression and neurodegeneration. The seizures are typically refractory and include febrile seizures, infantile spasms, focal seizures, and myoclonic seizures, and occur at frequencies of multiple seizures daily or hourly. Most patients develop hypotonia early in life and can develop peripheral limb hypertonia later. Additional features include issues with recurrent aspiration and feeding difficulties requiring enteral feeding. Findings from brain MRI are variable but include reduction in white matter volume, delayed myelination, thin corpus callosum and cerebral atrophy. Patients for whom CT scans are available all showed punctate calcifications of cerebral matter. A total of 9 variants, including 2 missense and 7 truncating variants, have been reported in 7 probands from 4 publications and are included in this curation (PMIDs: 32100099, 32197075, 35099671, 35716448). The mechanism of pathogenicity is reported to be biallelic loss of function. This gene-disease relationship is also supported by expression studies and mouse models which recapitulate the clinical phenotype (PMIDs: 32100099, 29909984, 32197075). In summary, NRROS is definitively associated with autosomal recessive early onset seizures with neurodegeneration and brain calcification. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 15th September 2023 (SOP Version 9.0).

Clinical Genomic Database (CGD)

Seizures, early-onset, with neurodegeneration and brain calcificationAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 32100099; 32197075

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NRROS variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 105

Seizures, early-onset, with neurodegeneration and brain calcificationsTotal: 20

not providedTotal: 19

not specifiedTotal: 6

NRROS-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198565.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				4 clinvar	2 clinvar	6
missense	2 clinvar		98 clinvar	18 clinvar	1 clinvar	119
nonsense	2 clinvar	3 clinvar				5
start loss						0
frameshift	3 clinvar	2 clinvar				5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	7	5	99	22	3	136

Highest pathogenic variant AF is 0.0000041045455

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198565.3	RefSeq	NP_940967.1	2	MANE Select
ENST00000328557.5	Ensembl	ENSP00000328625.4	2	MANE Select
ENST00000907983.1	Ensembl	ENSP00000578042.1	2	Standard
ENST00001129162.1	Ensembl	ENSP00000798967.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TYROBP Causal Network

Biological Process

superoxide metabolic process
inflammatory response
immune response
transforming growth factor beta receptor signaling pathway
microglia development

Molecular Function

transforming growth factor beta binding

Cellular Component

extracellular region
endoplasmic reticulum
endoplasmic reticulum membrane
plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328557
Coding exons: 2
Length: 22319
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125747
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.892	379	431	0.879	0.0000290	4473
Missense (PolyPhen)		77	115.03	0.66937		1475
Synonymous	-0.611	223	212	1.05	0.0000152	1531
Loss of Function	2.96	4	17.2	0.232	8.26e-7	181

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key regulator of transforming growth factor beta-1 (TGFB1) specifically required for microglia function in the nervous system (By similarity). Required for activation of latent TGF-beta-1 in macrophages and microglia: associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGFB1, and regulates integrin- dependent activation of TGF-beta-1 (By similarity). TGF-beta-1 activation mediated by LRRC33/NRROS is highly localized: there is little spreading of TGF-beta-1 activated from one microglial cell to neighboring microglia, suggesting the existence of localized and selective activation of TGF-beta-1 by LRRC33/NRROS (By similarity). Indirectly plays a role in Toll-like receptor (TLR) signaling: ability to inhibit TLR-mediated NF-kappa-B activation and cytokine production is probably a consequence of its role in TGF-beta-1 signaling (PubMed:23545260). {ECO:0000250|UniProtKB:Q8BMT4, ECO:0000269|PubMed:23545260}.;

Intolerance Scores

RVIS EVS: -0.68
RVIS percentile EVS: 15.36

Essentials

Essential (CRISPR): N
Essential (gene trap): K

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium