NPRL3

NPR3 like, GATOR1 complex subunit, the group of GATOR1 subcomplex

Basic information

Region (hg38): 16:84271-138677

Previous symbols: [ "C16orf35" ]

Links

ENSG00000103148 ∙ NCBI:8131 ∙ OMIM:600928 ∙ HGNC:14124 ∙ Uniprot:Q12980 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• focal epilepsy (Definitive), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 3 (Strong), mode of inheritance: AD
• familial focal epilepsy with variable foci (Supportive), mode of inheritance: AD
• epilepsy, familial focal, with variable foci 3 (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, familial focal, with variable foci 3	AD	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	26285051; 26505888; 27173016

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPRL3 gene.

• Epilepsy,_familial_focal,_with_variable_foci_3 (832 variants)
• not_provided (260 variants)
• Inborn_genetic_diseases (66 variants)
• not_specified (21 variants)
• NPRL3-related_disorder (20 variants)
• Seizure (7 variants)
• Epilepsy (2 variants)
• Epilepsy,_familial_focal,_with_variable_foci_1 (2 variants)
• Familial_focal_epilepsy_with_variable_foci (1 variants)
• Intellectual_disability (1 variants)
• Autosomal_dominant_nocturnal_frontal_lobe_epilepsy (1 variants)
• Focal_epilepsy (1 variants)
• Familial_temporal_lobe_epilepsy_2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPRL3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001077350.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	173	3	185
missense	2	3	362	28	4	399
nonsense	28	9	2			39
start loss						0
frameshift	46	12	11	1	1	71
splice donor/acceptor (+/-2bp)	11	29	3	2		45
Total	87	53	387	204	8

Highest pathogenic variant AF is 0.000012945001

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPRL3	protein_coding	protein_coding	ENST00000399953	14	54587

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		729	123969	7	124705	0.924

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.84	245	340	0.720	0.0000216	3661
Missense in Polyphen		65	93.976	0.69166		1084
Synonymous	-0.152	149	147	1.02	0.00000998	1131
Loss of Function	3.42	6	24.1	0.249	0.00000118	281

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	2.00	1.89
Ashkenazi Jewish	1.00	0.928
East Asian	1.00	0.955
Finnish	1.00	0.934
European (Non-Finnish)	1.00	0.913
Middle Eastern	1.00	0.955
South Asian	1.00	0.956
Other	1.00	0.917

dbNSFP

Source: dbNSFP

• Function: FUNCTION: As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway. {ECO:0000269|PubMed:23723238}.
• Disease: DISEASE: Epilepsy, familial focal, with variable foci 3 (FFEVF3) [MIM:617118]: An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. {ECO:0000269|PubMed:26285051, ECO:0000269|PubMed:26505888, ECO:0000269|PubMed:27173016}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: mTOR signaling pathway - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.147

Essentials

• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.731

Gene Damage Prediction

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

Gene ontology

• Biological process: ventricular septum development;negative regulation of TOR signaling;cellular response to amino acid starvation;aorta morphogenesis;TORC1 signaling;positive regulation of GTPase activity;cardiac muscle tissue development;roof of mouth development;regulation of autophagosome assembly
• Cellular component: lysosomal membrane;GATOR1 complex
• Molecular function: GTPase activator activity;protein binding