NPHP1

nephrocystin 1, the group of NPHP complex

Basic information

Region (hg38): 2:110122310-110205066

Previous symbols: [ "NPH1" ]

Links

ENSG00000144061 ∙ NCBI:4867 ∙ OMIM:607100 ∙ HGNC:7905 ∙ Uniprot:O15259 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nephronophthisis 1 (Definitive), mode of inheritance: AR
• Joubert syndrome with renal defect (Moderate), mode of inheritance: AR
• Senior-Loken syndrome (Supportive), mode of inheritance: AR
• Bardet-Biedl syndrome (Supportive), mode of inheritance: AR
• nephronophthisis 1 (Supportive), mode of inheritance: AR
• Joubert syndrome with renal defect (Supportive), mode of inheritance: AR
• Joubert syndrome with renal defect (Definitive), mode of inheritance: AR
• nephronophthisis 1 (Strong), mode of inheritance: AR
• nephronophthisis 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Joubert syndrome 4; Nephronophthisis 1; Senior-Loken syndrome 1	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	Hematologic; Neurologic; Ophthalmologic; Renal	14823504; 13763238; 13910672; 9326933; 9361039; 9856524; 10196704; 15138899; 16155189; 16571882; 20301500; 20454808; 20652329; 21068128; 21258817; 21866095; 23559409
The conditions may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial; Renal transplant has been described, though nephrotic syndrome may recur post-transplantation

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPHP1 gene.

• Nephronophthisis (549 variants)
• not provided (172 variants)
• Joubert syndrome with renal defect (99 variants)
• Nephronophthisis 1 (56 variants)
• Senior-Loken syndrome 1 (46 variants)
• not specified (31 variants)
• Inborn genetic diseases (31 variants)
• Joubert syndrome with renal defect;Nephronophthisis 1;Senior-Loken syndrome 1 (26 variants)
• Joubert syndrome with renal defect;Senior-Loken syndrome 1;Nephronophthisis 1 (15 variants)
• Senior-Loken syndrome 1;Joubert syndrome with renal defect;Nephronophthisis 1 (14 variants)
• Nephronophthisis 1;Senior-Loken syndrome 1;Joubert syndrome with renal defect (8 variants)
• Nephronophthisis 1;Joubert syndrome with renal defect;Senior-Loken syndrome 1 (7 variants)
• NPHP1-related condition (5 variants)
• Joubert syndrome and related disorders (5 variants)
• Senior-Loken syndrome 1;Nephronophthisis 1;Joubert syndrome with renal defect (3 variants)
• Kidney disorder (3 variants)
• NPHP1-Related Disorders (2 variants)
• Familial aplasia of the vermis (2 variants)
• Renal dysplasia and retinal aplasia (2 variants)
• Bardet-Biedl syndrome 1 (1 variants)
• Focal segmental glomerulosclerosis (1 variants)
• Joubert syndrome 1 (1 variants)
• Intellectual disability, X-linked 102 (1 variants)
• Leber congenital amaurosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPHP1 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	9	108	3	121
missense	1	1	260	7	2	271
nonsense	9	16				25
start loss						0
frameshift	24	11	1			36
inframe indel		1	4			5
splice donor/acceptor (+/-2bp)	7	22	2			31
splice region			23	21	1	45
non coding			13	85	36	134
Total	41	52	289	200	41

Highest pathogenic variant AF is 0.000118

Variants in NPHP1

This is a list of pathogenic ClinVar variants found in the NPHP1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-110123331-A-T		Joubert syndrome with renal defect • Senior-Loken syndrome 1 • Nephronophthisis 1	Uncertain significance (Jan 13, 2018)
2-110123452-GGTT-G		Familial aplasia of the vermis • Renal dysplasia and retinal aplasia • Nephronophthisis	Uncertain significance (Jun 14, 2016)
2-110123469-T-C		Senior-Loken syndrome 1 • Joubert syndrome with renal defect • Nephronophthisis 1	Uncertain significance (Jan 13, 2018)
2-110123541-G-A		Senior-Loken syndrome 1 • Joubert syndrome with renal defect • Nephronophthisis 1	Uncertain significance (Jan 12, 2018)
2-110123553-A-G		Joubert syndrome with renal defect • Nephronophthisis 1 • Senior-Loken syndrome 1	Uncertain significance (Jan 12, 2018)
2-110123585-G-C			Likely benign (Jun 01, 2022)
2-110123592-T-C		Senior-Loken syndrome 1 • Nephronophthisis 1 • Joubert syndrome with renal defect	Uncertain significance (Jan 12, 2018)
2-110123597-A-G		Joubert syndrome with renal defect • Nephronophthisis 1 • Senior-Loken syndrome 1	Conflicting classifications of pathogenicity (Jan 12, 2018)
2-110123790-G-A			Uncertain significance (Jun 20, 2017)
2-110123794-C-G		Nephronophthisis	Likely benign (Feb 05, 2023)
2-110123804-T-C		NPHP1-related disorder	Uncertain significance (Dec 15, 2023)
2-110123806-T-G		Nephronophthisis	Uncertain significance (Oct 27, 2021)
2-110123807-C-T		Nephronophthisis • Senior-Loken syndrome 1;Joubert syndrome with renal defect;Nephronophthisis 1	Uncertain significance (Sep 07, 2022)
2-110123808-T-G		Nephronophthisis	Likely benign (Sep 04, 2023)
2-110123815-A-G		Nephronophthisis	Likely benign (Nov 11, 2021)
2-110123818-C-T		Nephronophthisis • Senior-Loken syndrome 1;Nephronophthisis 1;Joubert syndrome with renal defect	Conflicting classifications of pathogenicity (Sep 01, 2023)
2-110123827-A-G		Nephronophthisis	Likely benign (Mar 07, 2023)
2-110123830-G-A		Nephronophthisis	Likely benign (Jan 10, 2024)
2-110123831-G-A		Nephronophthisis	Uncertain significance (Jul 20, 2022)
2-110123834-T-TG		Nephronophthisis	Uncertain significance (Apr 16, 2022)
2-110123847-CA-C		Nephronophthisis	Pathogenic (Dec 30, 2019)
2-110123859-G-A		Nephronophthisis	Uncertain significance (Oct 13, 2021)
2-110123865-C-T		Nephronophthisis • Joubert syndrome with renal defect;Nephronophthisis 1;Senior-Loken syndrome 1	Uncertain significance (Jul 06, 2022)
2-110123866-G-A		Nephronophthisis	Likely benign (Dec 09, 2023)
2-110123870-G-A		Nephronophthisis	Uncertain significance (Feb 27, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPHP1	protein_coding	protein_coding	ENST00000316534	20	82756

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.24e-17	0.428	125668	0	79	125747	0.000314

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.226	369	381	0.967	0.0000192	4814
Missense in Polyphen		127	143.75	0.88347		1953
Synonymous	0.777	124	136	0.915	0.00000727	1365
Loss of Function	1.69	33	45.2	0.729	0.00000216	533

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00126	0.00126
Ashkenazi Jewish	0.00	0.00
East Asian	0.000490	0.000489
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000239	0.000237
Middle Eastern	0.000490	0.000489
South Asian	0.000267	0.000261
Other	0.000328	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Together with BCAR1 it may play a role in the control of epithelial cell polarity. Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling. May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development. In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis (By similarity). {ECO:0000250}.
• Disease: DISEASE: Nephronophthisis 1 (NPHP1) [MIM:256100]: An autosomal recessive inherited disease characterized by anemia, polyuria, polydipsia, isosthenuria and death in uremia. Symmetrical destruction of the kidneys involving both tubules and glomeruli occurs. The underlying pathology is a chronic tubulo-interstitial nephropathy with characteristic tubular basement membrane thickening and medullary cyst formation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. The age at death ranges from about 4 to 15 years. {ECO:0000269|PubMed:10839884}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Senior-Loken syndrome 1 (SLSN1) [MIM:266900]: A renal- retinal disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. {ECO:0000269|PubMed:9856524}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 4 (JBTS4) [MIM:609583]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. Joubert syndrome type 4 is a phenotypically mild form. {ECO:0000269|PubMed:15138899, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Anchoring of the basal body to the plasma membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.178

Intolerance Scores

• loftool: 0.993
• rvis_EVS: 0.07
• rvis_percentile_EVS: 58.96

Haploinsufficiency Scores

• pHI: 0.109
• hipred: N
• hipred_score: 0.485
• ghis: 0.477

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.541

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nphp1
• Phenotype: endocrine/exocrine gland phenotype; cellular phenotype; reproductive system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype

Zebrafish Information Network

• Gene name: nphp1
• Affected structure: pronephric proximal convoluted tubule
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: signal transduction;excretion;visual behavior;cell projection organization;actin cytoskeleton organization;spermatid differentiation;retina development in camera-type eye;ciliary basal body-plasma membrane docking;cell-cell adhesion;positive regulation of bicellular tight junction assembly
• Cellular component: cytosol;cytoskeleton;cell-cell junction;adherens junction;bicellular tight junction;membrane;motile cilium;photoreceptor connecting cilium
• Molecular function: structural molecule activity;protein binding