NRROS

negative regulator of reactive oxygen species

Basic information

Region (hg38): 3:196639694-196662004

Previous symbols: [ "LRRC33" ]

Links

ENSG00000174004 ∙ NCBI:375387 ∙ OMIM:615322 ∙ HGNC:24613 ∙ Uniprot:Q86YC3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• seizures, early-onset, with neurodegeneration and brain calcifications (Strong), mode of inheritance: AR
• seizures, early-onset, with neurodegeneration and brain calcifications (Moderate), mode of inheritance: AR
• seizures, early-onset, with neurodegeneration and brain calcifications (Strong), mode of inheritance: AR
• seizures, early-onset, with neurodegeneration and brain calcifications (Strong), mode of inheritance: AR
• seizures, early-onset, with neurodegeneration and brain calcifications (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Seizures, early-onset, with neurodegeneration and brain calcification	AR	General	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	Neurologic	32100099; 32197075

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NRROS gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NRROS gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				1	2	3
missense			40	4	2	46
nonsense		2				2
start loss						0
frameshift		2				2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding						0
Total	0	4	40	5	4

Variants in NRROS

This is a list of pathogenic ClinVar variants found in the NRROS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-196654568-T-C		Seizures, early-onset, with neurodegeneration and brain calcifications	Pathogenic (May 15, 2020)
3-196654604-G-A		Inborn genetic diseases	Uncertain significance (Aug 01, 2022)
3-196654609-G-A		Inborn genetic diseases • Seizures, early-onset, with neurodegeneration and brain calcifications	Uncertain significance (Dec 13, 2023)
3-196659748-G-A		Seizures, early-onset, with neurodegeneration and brain calcifications	Uncertain significance (Jan 05, 2023)
3-196659777-G-A		Inborn genetic diseases	Uncertain significance (Dec 02, 2021)
3-196659804-G-A		Inborn genetic diseases	Likely benign (Jun 07, 2024)
3-196659817-C-A		Inborn genetic diseases	Uncertain significance (Dec 02, 2022)
3-196659822-G-A		Seizures, early-onset, with neurodegeneration and brain calcifications • Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 24, 2022)
3-196659828-T-C		Seizures, early-onset, with neurodegeneration and brain calcifications	Pathogenic (Oct 12, 2021)
3-196659830-AC-A		Seizures, early-onset, with neurodegeneration and brain calcifications	Pathogenic (May 15, 2020)
3-196659923-G-C		Inborn genetic diseases	Uncertain significance (Sep 12, 2023)
3-196659929-A-G		Inborn genetic diseases	Uncertain significance (Jan 24, 2023)
3-196659935-C-T		Inborn genetic diseases	Uncertain significance (Nov 15, 2021)
3-196659953-C-T		Seizures, early-onset, with neurodegeneration and brain calcifications	Pathogenic (Oct 12, 2021)
3-196659965-C-T		Inborn genetic diseases	Uncertain significance (Dec 21, 2023)
3-196660000-G-T		Inborn genetic diseases	Uncertain significance (Aug 12, 2021)
3-196660005-A-C		Inborn genetic diseases	Uncertain significance (Feb 15, 2023)
3-196660064-G-C		Inborn genetic diseases	Uncertain significance (Sep 13, 2023)
3-196660093-C-G		Seizures, early-onset, with neurodegeneration and brain calcifications	Benign (Sep 05, 2021)
3-196660094-C-A		Inborn genetic diseases	Uncertain significance (Nov 17, 2022)
3-196660187-C-A			Benign (May 14, 2018)
3-196660193-C-T		Inborn genetic diseases	Uncertain significance (Jul 11, 2023)
3-196660250-G-A		Inborn genetic diseases	Likely benign (Mar 07, 2024)
3-196660332-T-A		Inborn genetic diseases	Uncertain significance (Apr 15, 2024)
3-196660340-G-A		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NRROS	protein_coding	protein_coding	ENST00000328557	2	22319

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.326	0.674	125733	0	14	125747	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.892	379	431	0.879	0.0000290	4473
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000617	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000797	0.0000791
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000981	0.0000980
Other	0.00	0.00

dbNSFP

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}.
• Pathway: TYROBP Causal Network (Consensus)

Intolerance Scores

• rvis_EVS: -0.68
• rvis_percentile_EVS: 15.36

Haploinsufficiency Scores

• pHI: 0.417
• hipred: Y
• hipred_score: 0.631
• ghis: 0.548

Essentials

• essential_gene_CRISPR: N
• essential_gene_gene_trap: K

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nrros
• Phenotype: cellular phenotype; immune system phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: superoxide metabolic process;inflammatory response;immune response;transforming growth factor beta receptor signaling pathway;microglia development;sequestering of TGFbeta in extracellular matrix;transforming growth factor beta1 activation;innate immune response
• Cellular component: extracellular region;endoplasmic reticulum;endoplasmic reticulum membrane;plasma membrane;cell surface;integral component of membrane
• Molecular function: transforming growth factor beta binding