NPHP4

nephrocystin 4, the group of NPHP complex

Basic information

Region (hg38): 1:5862810-5992473

Links

ENSG00000131697 ∙ NCBI:261734 ∙ OMIM:607215 ∙ HGNC:19104 ∙ Uniprot:O75161 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nephronophthisis 4 (Definitive), mode of inheritance: AR
• Senior-Loken syndrome (Supportive), mode of inheritance: AR
• nephronophthisis 1 (Supportive), mode of inheritance: AR
• Senior-Loken syndrome 4 (Definitive), mode of inheritance: AR
• nephronophthisis 4 (Strong), mode of inheritance: AR
• Senior-Loken syndrome 4 (Strong), mode of inheritance: AR
• nephronophthisis 4 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Nephronophthisis 4; Senior-Loken syndrome 4	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	Ophthalmologic; Renal	12205563; 11920287; 12244321; 21068128; 21866095
Avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPHP4 gene.

• Nephronophthisis (1279 variants)
• not provided (431 variants)
• Nephronophthisis 4 (184 variants)
• Nephronophthisis 4;Senior-Loken syndrome 4 (178 variants)
• Senior-Loken syndrome 4 (163 variants)
• not specified (90 variants)
• Inborn genetic diseases (83 variants)
• Senior-Loken syndrome 4;Nephronophthisis 4 (79 variants)
• NPHP4-related condition (28 variants)
• Kidney disorder (26 variants)
• Retinal dystrophy (7 variants)
• Bardet-Biedl syndrome (5 variants)
• Renal dysplasia and retinal aplasia (5 variants)
• NPHP4-Related Disorders (4 variants)
• Retinitis pigmentosa (2 variants)
• Leber congenital amaurosis (2 variants)
• Focal segmental glomerulosclerosis (1 variants)
• Cerebello-oculo-renal syndrome (nephronophthisis, oculomotor apraxia and cerebellar abnormalities);Infertility disorder (1 variants)
• Congenital anomaly of kidney and urinary tract (1 variants)
• Atypical hemolytic-uremic syndrome (1 variants)
• Cholestasis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPHP4 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			25	226	9	260
missense		1	671	17	7	696
nonsense	21	6	1			28
start loss						0
frameshift	23	17	2			42
inframe indel			10			10
splice donor/acceptor (+/-2bp)	6	19	2		1	28
splice region			37	42		79
non coding			17	121	60	198
Total	50	43	728	364	77

Highest pathogenic variant AF is 0.000144

Variants in NPHP4

This is a list of pathogenic ClinVar variants found in the NPHP4 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-5862951-A-C		Nephronophthisis 4 • Senior-Loken syndrome 4	Benign (Jan 13, 2018)
1-5862980-C-T		Nephronophthisis 4 • Senior-Loken syndrome 4	Uncertain significance (Jan 13, 2018)
1-5863137-T-G		Nephronophthisis 4 • Senior-Loken syndrome 4	Benign (Jan 13, 2018)
1-5863168-A-T		Senior-Loken syndrome 4 • Nephronophthisis 4	Uncertain significance (Jan 12, 2018)
1-5863178-G-C		Senior-Loken syndrome 4 • Nephronophthisis 4	Uncertain significance (Jan 13, 2018)
1-5863239-G-A		Nephronophthisis 4 • Senior-Loken syndrome 4	Uncertain significance (Jan 13, 2018)
1-5863277-G-A		Nephronophthisis	Likely benign (Mar 27, 2022)
1-5863279-C-G		Nephronophthisis	Uncertain significance (Jul 23, 2022)
1-5863279-C-T		Nephronophthisis	Uncertain significance (Feb 22, 2021)
1-5863285-C-T		Nephronophthisis • Senior-Loken syndrome 4;Nephronophthisis 4 • NPHP4-related disorder	Uncertain significance (Nov 18, 2023)
1-5863286-G-A		Nephronophthisis	Likely benign (Sep 21, 2023)
1-5863295-C-T		NPHP4-related disorder	Likely benign (May 06, 2022)
1-5863297-C-T		Nephronophthisis	Uncertain significance (Aug 22, 2022)
1-5863300-C-T		Nephronophthisis	Uncertain significance (May 16, 2022)
1-5863301-G-A		Nephronophthisis	Likely benign (May 25, 2022)
1-5863307-G-C		Senior-Loken syndrome 4;Nephronophthisis 4 • Nephronophthisis	Uncertain significance (Sep 27, 2022)
1-5863309-C-T		Senior-Loken syndrome 4 • Nephronophthisis • Nephronophthisis 4 • not specified	Benign/Likely benign (Jan 25, 2024)
1-5863313-A-G		Nephronophthisis	Conflicting classifications of pathogenicity (Jan 26, 2024)
1-5863314-T-C		Nephronophthisis	Uncertain significance (Aug 30, 2021)
1-5863321-T-C		Nephronophthisis	Uncertain significance (Mar 12, 2022)
1-5863324-T-C		Nephronophthisis	Uncertain significance (Sep 15, 2021)
1-5863325-G-A		Nephronophthisis	Conflicting classifications of pathogenicity (Nov 08, 2022)
1-5863326-T-C		Senior-Loken syndrome 4;Nephronophthisis 4	Uncertain significance (Mar 02, 2022)
1-5863329-A-C		Nephronophthisis	Uncertain significance (Oct 21, 2021)
1-5863335-A-G			Uncertain significance (Nov 18, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPHP4	protein_coding	protein_coding	ENST00000378156	29	129663

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.74e-29	0.0273	124517	1	193	124711	0.000778

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.242	910	890	1.02	0.0000593	9106
Missense in Polyphen		260	281.88	0.92239		3111
Synonymous	-1.57	437	397	1.10	0.0000290	2975
Loss of Function	1.67	53	67.8	0.782	0.00000377	710

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00190	0.00185
Ashkenazi Jewish	0.00113	0.000994
East Asian	0.000726	0.000723
Finnish	0.0000931	0.0000928
European (Non-Finnish)	0.000724	0.000681
Middle Eastern	0.000726	0.000723
South Asian	0.00157	0.00154
Other	0.00118	0.00115

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module (PubMed:19755384, PubMed:21565611). Does not seem to be strictly required for ciliogenesis (PubMed:21565611). Required for building functional cilia. Involved in the organization of the subapical actin network in multiciliated epithelial cells. Seems to recruit INT to basal bodies of motile cilia which subsequently interacts with actin-modifying proteins such as DAAM1 (By similarity). In cooperation with INVS may downregulate the canonical Wnt pathway and promote the Wnt-PCP pathway by regulating expression and subcellular location of disheveled proteins. Stabilizes protein levels of JADE1 and promotes its translocation to the nucleus leading to cooperative inhibition of canonical Wnt signaling (PubMed:21498478, PubMed:22654112). Acts as negative regulator of the hippo pathway by association with LATS1 and modifying LATS1- dependent phosphorylation and localization of WWTR1/TAZ (PubMed:21555462). {ECO:0000250|UniProtKB:B0DOB4, ECO:0000250|UniProtKB:P59240, ECO:0000269|PubMed:21498478, ECO:0000269|PubMed:21555462, ECO:0000269|PubMed:21565611, ECO:0000269|PubMed:22654112, ECO:0000305|PubMed:19755384}.
• Disease: DISEASE: Note=Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome, including NPHP4, influence the clinical outcome (PubMed:21258341). {ECO:0000269|PubMed:21258341}.; DISEASE: Senior-Loken syndrome 4 (SLSN4) [MIM:606996]: 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:12244321, ECO:0000269|PubMed:15776426, ECO:0000269|PubMed:21546380, ECO:0000269|PubMed:22550138}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=May be involved in male infertility. Homozygosity for a frameshift truncating mutation are associated with markedly abnormal sperm morphology. {ECO:0000269|PubMed:23574405}.; DISEASE: Note=May be involved in cardiac laterality defects and heterotaxy. Homozygosity for a frameshift truncating mutation are associated with markedly abnormal sperm morphology. {ECO:0000305|PubMed:22550138}.
• Pathway: Signal Transduction;Signaling by Hippo;Anchoring of the basal body to the plasma membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.168

Intolerance Scores

• loftool: 0.0210
• rvis_EVS: 0.57
• rvis_percentile_EVS: 81.79

Haploinsufficiency Scores

• pHI: 0.123
• hipred: N
• hipred_score: 0.266
• ghis: 0.589

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.916

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nphp4
• Phenotype: cellular phenotype; pigmentation phenotype; reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye 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)

Zebrafish Information Network

• Gene name: nphp4
• Affected structure: posterior pronephric duct
• Phenotype tag: abnormal
• Phenotype quality: bent

Gene ontology

• Biological process: signal transduction;visual behavior;actin cytoskeleton organization;flagellated sperm motility;hippo signaling;photoreceptor cell outer segment organization;photoreceptor cell maintenance;retina development in camera-type eye;negative regulation of canonical Wnt signaling pathway;ciliary basal body-plasma membrane docking;cell-cell adhesion;positive regulation of bicellular tight junction assembly
• Cellular component: nucleus;centrosome;cytosol;cell-cell junction;bicellular tight junction;photoreceptor connecting cilium;ciliary basal body;ribbon synapse;ciliary base
• Molecular function: structural molecule activity;protein binding