NPHP3

Summary

NPHP3 (nephrocystin 3, HGNC:7907) is a protein-coding gene on chromosome 3q22.1, encoding Nephrocystin-3 (Q7Z494). Required for normal ciliary development and function.

This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene.

Source: NCBI Gene 27031 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephronophthisis (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 1,094 total — 73 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 92
• MANE Select transcript: NM_153240

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7907
Approved symbol	NPHP3
Name	nephrocystin 3
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	NPH3, KIAA2000, FLJ30691, FLJ36696, MKS7, SLSN3, CFAP31
Ensembl gene	ENSG00000113971
Ensembl biotype	protein_coding
OMIM	608002
Entrez	27031

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 6 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000337331, ENST00000383282, ENST00000465756, ENST00000469232, ENST00000471145, ENST00000474871, ENST00000476742, ENST00000490993, ENST00000493732, ENST00000512094, ENST00000515289, ENST00000683570, ENST00000684294, ENST00000684756, ENST00000971412, ENST00000971413

RefSeq mRNA: 1 — MANE Select: NM_153240 NM_153240

CCDS: CCDS3078

Canonical transcript exons

ENST00000337331 — 27 exons

Exon	Start	End
ENSE00001810363	132721963	132722409
ENSE00002366083	132699353	132699450
ENSE00003468063	132684554	132684794
ENSE00003475666	132692654	132692818
ENSE00003486742	132688650	132688891
ENSE00003536534	132691192	132691286
ENSE00003538042	132686260	132686387
ENSE00003544555	132682703	132682818
ENSE00003548396	132680609	132682090
ENSE00003563721	132697260	132697362
ENSE00003572261	132696731	132696813
ENSE00003573197	132690528	132690650
ENSE00003592797	132689074	132689263
ENSE00003607729	132687151	132687226
ENSE00003633093	132683399	132683524
ENSE00003689983	132694827	132694965
ENSE00003712317	132705740	132705814
ENSE00003720654	132701430	132701533
ENSE00003722942	132715085	132715218
ENSE00003723750	132704198	132704371
ENSE00003726129	132708101	132708257
ENSE00003734049	132713126	132713286
ENSE00003736592	132700334	132700448
ENSE00003742587	132719705	132719830
ENSE00003743678	132699918	132700061
ENSE00003751811	132716757	132716909
ENSE00003752954	132718994	132719144

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 95.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9729 / max 174.2108, expressed in 1785 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44634	14.9729	1785

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
superficial temporal artery	UBERON:0001614	95.42	gold quality
layer of synovial tissue	UBERON:0007616	94.62	gold quality
left ovary	UBERON:0002119	94.54	gold quality
thymus	UBERON:0002370	94.04	gold quality
right uterine tube	UBERON:0001302	93.73	gold quality
calcaneal tendon	UBERON:0003701	93.41	gold quality
urethra	UBERON:0000057	93.12	gold quality
right ovary	UBERON:0002118	92.83	gold quality
endocervix	UBERON:0000458	92.72	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.11	gold quality
body of uterus	UBERON:0009853	92.09	gold quality
tibial nerve	UBERON:0001323	92.03	gold quality
sural nerve	UBERON:0015488	92.00	gold quality
visceral pleura	UBERON:0002401	91.97	gold quality
buccal mucosa cell	CL:0002336	91.66	gold quality
ovary	UBERON:0000992	91.57	gold quality
renal medulla	UBERON:0000362	91.47	gold quality
mucosa of stomach	UBERON:0001199	91.40	gold quality
uterine cervix	UBERON:0000002	91.37	gold quality
tibia	UBERON:0000979	91.07	gold quality
cardia of stomach	UBERON:0001162	91.04	gold quality
thyroid gland	UBERON:0002046	91.04	gold quality
left lobe of thyroid gland	UBERON:0001120	90.87	gold quality
descending thoracic aorta	UBERON:0002345	90.86	gold quality
body of pancreas	UBERON:0001150	90.84	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.81	gold quality
synovial joint	UBERON:0002217	90.78	gold quality
corpus callosum	UBERON:0002336	90.77	gold quality
trigeminal ganglion	UBERON:0001675	90.70	gold quality
right lobe of thyroid gland	UBERON:0001119	90.60	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.08
E-CURD-7	no	124.29
E-ENAD-21	no	124.29
E-MTAB-7606	no	68.48

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting NPHP3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4458	99.96	71.64	1650
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942

Literature-anchored findings (GeneRIF, showing 16)

• Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. (PMID:12872122)
• In six families with nephronophthisis, there were two mutations in either NPHP1, NPHP3, or NPHP4, suggesting oligogenicity. (PMID:17855640)
• NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects. (PMID:18371931)
• screened 43 families with infantile nephronophthisis (ESRD less than 5 years of age) for NPHP2 and NPHP3 mutations and determined genotype-phenotype correlations (PMID:19177160)
• The presence of congenital malformations in the case series confirms the crucial role of NPHP3 in early embryonic development of the kidneys and urinary tract. (PMID:19303681)
• The known phenotype of NPHP3 mutation caused renal-hepatic-pancreatic dysplasia has been extended to include skeletal and CNS anomalies. (PMID:23686967)
• ANKS6 as a new NPHP family member that assembles a distinct module of nephronophthisis-associated proteins, encompassing NEK8, INVS and NPHP3. (PMID:23793029)
• a rare neonatal ciliopathy presentation of NPHP3 mutations leading to severe multiorgan failure in two siblings. (PMID:24776604)
• NPHP3 mutations were prevalent in Chinese infantile nephronophthisis patients. All patients with NPHP3 mutations showed renal-hepatic phenotype. (PMID:26184788)
• Inherited 3 deleterious mutations in two nephronophthisis genes, NPHP3 and NPHP4 cause unusually severe form of infantile nephronophthisis. (PMID:28392475)
• Case Report: NPHP3 related nephronophthisis manifesting in the fetal period. (PMID:28921755)
• Thymosin beta-4 is a novel regulator for primary cilium formation by nephronophthisis 3 in HeLa human cervical cancer cells. (PMID:31048733)
• Clinical and pathological features and varied mutational spectra of pathogenic genes in 55 Chinese patients with nephronophthisis. (PMID:32173348)
• A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families. (PMID:34212438)
• HeLa Cervical Cancer Cells Are Maintained by Nephronophthisis 3-Associated Primary Cilium Formation via ROS-Induced ERK and HIF-1alpha Activation under Serum-Deprived Normoxic Condition. (PMID:36498831)
• Vinblastine Resistance Is Associated with Nephronophthisis 3-Mediated Primary Cilia via Intraflagellar Transport Protein 88 and Apoptosis-Antagonizing Transcription Factor. (PMID:39408701)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nphp3	ENSDARG00000078261
mus_musculus	Nphp3	ENSMUSG00000032558
rattus_norvegicus	Nphp3	ENSRNOG00000048978

Paralogs (5): APPBP2 (ENSG00000062725), KLC3 (ENSG00000104892), KLC1 (ENSG00000126214), KLC4 (ENSG00000137171), KLC2 (ENSG00000174996)

Protein

Protein identifiers

Nephrocystin-3 — Q7Z494 (reviewed: Q7Z494)

All UniProt accessions (4): Q7Z494, A0A0C4DG93, F2Z3A8, H0YAM4

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal ciliary development and function. Inhibits disheveled-1-induced canonical Wnt-signaling activity and may also play a role in the control of non-canonical Wnt signaling which regulates planar cell polarity. Probably acts as a molecular switch between different Wnt signaling pathways. Required for proper convergent extension cell movements.

Subunit / interactions. Interacts with NPHP1 and INVS/NPHP2. Interacts (when myristoylated) with UNC119 and UNC119B; interaction is required for localization to cilium. Interacts with CEP164. Component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3. ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme.

Subcellular location. Cell projection. Cilium.

Tissue specificity. Widely expressed at low level. Expressed in heart, placenta, liver, skeletal muscle, kidney and pancreas. Expressed at very low level in brain and lung.

Disease relevance. Nephronophthisis 3 (NPHP3) [MIM:604387] An autosomal recessive disorder resulting in end-stage renal disease. It is characterized by polyuria, polydipsia, anemia. Onset of terminal renal failure occurr significantly later (median age, 19 years) than in juvenile nephronophthisis. Renal pathology is characterized by alterations of tubular basement membranes, tubular atrophy and dilation, sclerosing tubulointerstitial nephropathy, and renal cyst development predominantly at the corticomedullary junction. The disease is caused by variants affecting the gene represented in this entry. Renal-hepatic-pancreatic dysplasia 1 (RHPD1) [MIM:208540] A disease characterized by cystic malformations of the kidneys, liver, and pancreas. The pathological findings consist of multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, a dysplastic pancreas with dilated ducts, cysts, fibrosis and inflammatory infiltrates. The disease is caused by variants affecting the gene represented in this entry. Meckel syndrome 7 (MKS7) [MIM:267010] A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (7)

UniProt ID	Names	Canonical?
Q7Z494-1	1	yes
Q7Z494-2	2
Q7Z494-3	3
Q7Z494-4	4
Q7Z494-5	5
Q7Z494-6	6
Q7Z494-7	7

RefSeq proteins (1): NP_694972* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR056883	NPHP3_hel	Domain
IPR056884	NPHP3-like_N	Domain
IPR056885	TPR_NPHP3	Domain
IPR056886	NPHP3_ab_dom	Domain

Pfam: PF13176, PF13424, PF24883, PF24884, PF24885, PF25022

UniProt features (40 total): splice variant 12, repeat 11, sequence variant 9, initiator methionine 1, chain 1, region of interest 1, coiled-coil region 1, compositionally biased region 1, lipid moiety-binding region 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5L7K	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z494-F1	73.59	0.09

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5624138	Trafficking of myristoylated proteins to the cilium

MSigDB gene sets: 373 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_PANCREAS_DEVELOPMENT, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (24): kidney development (GO:0001822), heart looping (GO:0001947), atrial septum development (GO:0003283), lipid metabolic process (GO:0006629), establishment or maintenance of cell polarity (GO:0007163), determination of left/right symmetry (GO:0007368), Wnt signaling pathway (GO:0016055), extracellular matrix organization (GO:0030198), lung development (GO:0030324), determination of pancreatic left/right asymmetry (GO:0035469), photoreceptor cell maintenance (GO:0045494), maintenance of animal organ identity (GO:0048496), convergent extension (GO:0060026), convergent extension involved in gastrulation (GO:0060027), cilium assembly (GO:0060271), epithelial cilium movement involved in determination of left/right asymmetry (GO:0060287), kidney morphogenesis (GO:0060993), determination of intestine left/right asymmetry (GO:0071908), determination of stomach left/right asymmetry (GO:0071909), determination of liver left/right asymmetry (GO:0071910), ureter development (GO:0072189), negative regulation of canonical Wnt signaling pathway (GO:0090090), non-motile cilium assembly (GO:1905515), regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000095)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), cytosol (GO:0005829), cilium (GO:0005929), ciliary inversin compartment (GO:0097543), ciliary base (GO:0097546), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cargo trafficking to the periciliary membrane	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
animal organ development	3
determination of left/right symmetry	3
determination of digestive tract left/right asymmetry	2
cilium	2
renal system development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
cardiac atrium development	1
cardiac septum development	1
primary metabolic process	1
cellular process	1
determination of bilateral symmetry	1
left/right pattern formation	1
cell surface receptor signaling pathway	1
extracellular structure organization	1
external encapsulating structure organization	1
respiratory tube development	1
respiratory system development	1
pancreas development	1
retina homeostasis	1
multicellular organismal process	1
negative regulation of cell differentiation	1
morphogenesis of an epithelium	1
gastrulation	1
embryonic morphogenesis	1
convergent extension	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
epithelial cilium movement involved in extracellular fluid movement	1
kidney development	1
animal organ morphogenesis	1
stomach development	1
liver development	1

Protein interactions and networks

STRING

2140 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPHP3	NEK8	Q86SG6	992
NPHP3	NPHP4	O75161	984
NPHP3	NPHP1	O15259	983
NPHP3	NEK9	Q8TD19	973
NPHP3	INVS	Q9Y283	973
NPHP3	ANKS6	Q68DC2	973
NPHP3	IQCB1	Q15051	948
NPHP3	RPGRIP1L	Q68CZ1	940
NPHP3	CEP290	O15078	915
NPHP3	SDCCAG8	Q86SQ7	884
NPHP3	TMEM67	Q5HYA8	863
NPHP3	BBS4	Q96RK4	748
NPHP3	PKHD1	P08F94	747
NPHP3	UNC119	Q13432	745
NPHP3	UNC119B	A6NIH7	745

IntAct

53 interactions, top by confidence:

A	B	Type	Score
UNC119	ARL2	psi-mi:“MI:0914”(association)	0.920
NPHP3	UNC119	psi-mi:“MI:0407”(direct interaction)	0.810
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
NUP62CL	OGT	psi-mi:“MI:0914”(association)	0.740
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
NPHP3	UNC119B	psi-mi:“MI:0914”(association)	0.590
UNC119B	NPHP3	psi-mi:“MI:0407”(direct interaction)	0.590
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
CASTOR3P	SNX2	psi-mi:“MI:0914”(association)	0.530
ZNF517	GGPS1	psi-mi:“MI:0914”(association)	0.530
UNC119	PDE8A	psi-mi:“MI:0914”(association)	0.530
CREB3	MYO9A	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
SNX11	PML	psi-mi:“MI:0914”(association)	0.530
NPHP3	OGT	psi-mi:“MI:0914”(association)	0.510
RUVBL1	NPHP3	psi-mi:“MI:0915”(physical association)	0.400
CEP164	NPHP3	psi-mi:“MI:0915”(physical association)	0.400
NPHP3	CEP164	psi-mi:“MI:0915”(physical association)	0.400
NPHP3	rep	psi-mi:“MI:0915”(physical association)	0.370
ATXN1	NPHP3	psi-mi:“MI:0915”(physical association)	0.370
Uso1	GOLGA2	psi-mi:“MI:0914”(association)	0.350
Ncapg2		psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (82): NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), ARHGEF35 (Affinity Capture-MS)

ESM2 similar proteins: A0A072VIM5, A0A0K0PU92, A0JM23, A2CIR7, F4IG73, F4JD14, G3LSH3, G8GTN7, O00750, O42132, O75460, O80560, P03372, P0CI65, P50241, P50242, P57717, P57753, Q0JJ01, Q29040, Q2HW56, Q2QXZ2, Q2RAQ5, Q53AD2, Q5D0W8, Q5M9H0, Q5YLM1, Q5ZLG9, Q6AZT7, Q6KAE5, Q6NLQ8, Q6PJI9, Q6WQJ1, Q7EZ44, Q7T0L6, Q7TNH6, Q7XAP4, Q7Z494, Q8C0M0, Q8CFE5

Diamond homologs: A0JM23, P0CI65, Q6AZT7, Q7TNH6, Q7Z494

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1094 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	73
Likely pathogenic	37
Uncertain significance	496
Likely benign	339
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069581	NM_153240.5(NPHP3):c.3402_3403del (p.Ala1135fs)	Pathogenic
1070327	NM_153240.5(NPHP3):c.1911G>A (p.Trp637Ter)	Pathogenic
1070974	NM_153240.5(NPHP3):c.2387G>A (p.Trp796Ter)	Pathogenic
1071083	NM_153240.5(NPHP3):c.30del (p.Ala11fs)	Pathogenic
1071323	NM_153240.5(NPHP3):c.2880_2883del (p.Ser960fs)	Pathogenic
1074908	NM_153240.5(NPHP3):c.2040del (p.Ile680_Ile681insTer)	Pathogenic
1376656	NM_153240.5(NPHP3):c.3439G>T (p.Glu1147Ter)	Pathogenic
1391319	NM_153240.5(NPHP3):c.1164del (p.Gly389fs)	Pathogenic
1410318	NM_153240.5(NPHP3):c.2985C>G (p.Tyr995Ter)	Pathogenic
1452385	NM_153240.5(NPHP3):c.2111_2112del (p.Cys704fs)	Pathogenic
1452823	NM_153240.5(NPHP3):c.3787del (p.Thr1263fs)	Pathogenic
1454798	NM_153240.5(NPHP3):c.1832_1833del (p.Ser611fs)	Pathogenic
1455660	NM_153240.5(NPHP3):c.707_716del (p.Ala236fs)	Pathogenic
1456839	NC_000003.11:g.(?132379382)(132441199_?)del	Pathogenic
1458848	NM_153240.5(NPHP3):c.1040dup (p.Asn347fs)	Pathogenic
1899117	NM_153240.5(NPHP3):c.2702_2703del (p.Phe901fs)	Pathogenic
1924475	NM_153240.5(NPHP3):c.391C>T (p.Gln131Ter)	Pathogenic
195423	NM_153240.5(NPHP3):c.434_437del (p.Glu145fs)	Pathogenic
195630	NM_153240.5(NPHP3):c.2994G>A (p.Trp998Ter)	Pathogenic
1972255	NM_153240.5(NPHP3):c.3576del (p.Lys1192fs)	Pathogenic
1976581	NM_153240.5(NPHP3):c.3255_3256dup (p.Gly1086fs)	Pathogenic
2019407	NM_153240.5(NPHP3):c.1289C>G (p.Ser430Ter)	Pathogenic
2046968	NM_153240.5(NPHP3):c.457C>T (p.Gln153Ter)	Pathogenic
2126113	NM_153240.5(NPHP3):c.1706C>G (p.Ser569Ter)	Pathogenic
2149097	NM_153240.5(NPHP3):c.2218C>T (p.Gln740Ter)	Pathogenic
216011	NM_153240.5(NPHP3):c.988G>A (p.Glu330Lys)	Pathogenic
2200352	NM_153240.5(NPHP3):c.1094_1098del (p.Leu365fs)	Pathogenic
2427428	NC_000003.11:g.(?132410016)(132411682_?)del	Pathogenic
2634	NM_153240.5(NPHP3):c.1381G>T (p.Glu461Ter)	Pathogenic
2636	NM_153240.5(NPHP3):c.1729C>T (p.Arg577Ter)	Pathogenic

SpliceAI

4145 predictions. Top by Δscore:

Variant	Effect	Δscore
3:132682086:CATAG:C	acceptor_gain	1.0000
3:132682091:C:CC	acceptor_gain	1.0000
3:132682092:T:C	acceptor_gain	1.0000
3:132682093:T:C	acceptor_gain	1.0000
3:132682093:T:TC	acceptor_gain	1.0000
3:132682820:T:C	acceptor_gain	1.0000
3:132682820:T:TC	acceptor_gain	1.0000
3:132682823:T:TC	acceptor_gain	1.0000
3:132683392:AACTT:A	donor_loss	1.0000
3:132683393:ACTT:A	donor_loss	1.0000
3:132683394:CTT:C	donor_loss	1.0000
3:132683395:TTAC:T	donor_loss	1.0000
3:132683396:TA:T	donor_loss	1.0000
3:132683397:A:AC	donor_gain	1.0000
3:132683397:AC:A	donor_gain	1.0000
3:132683398:C:CT	donor_gain	1.0000
3:132683398:CC:C	donor_gain	1.0000
3:132683398:CCA:C	donor_gain	1.0000
3:132683398:CCAT:C	donor_gain	1.0000
3:132683398:CCATT:C	donor_gain	1.0000
3:132683520:TTCCC:T	acceptor_gain	1.0000
3:132683521:TCCC:T	acceptor_gain	1.0000
3:132683522:CCC:C	acceptor_gain	1.0000
3:132683522:CCCC:C	acceptor_gain	1.0000
3:132683523:CC:C	acceptor_gain	1.0000
3:132683523:CCC:C	acceptor_gain	1.0000
3:132683524:CC:C	acceptor_gain	1.0000
3:132683524:CCTA:C	acceptor_loss	1.0000
3:132683525:C:CC	acceptor_gain	1.0000
3:132683525:C:T	acceptor_gain	1.0000

AlphaMissense

8712 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:132697358:A:G	W664R	0.999
3:132697358:A:T	W664R	0.999
3:132699357:A:G	W661R	0.999
3:132699357:A:T	W661R	0.999
3:132699429:A:G	W637R	0.999
3:132699429:A:T	W637R	0.999
3:132719708:G:C	F172L	0.999
3:132719708:G:T	F172L	0.999
3:132719709:A:G	F172S	0.999
3:132719710:A:G	F172L	0.999
3:132719826:A:G	L133P	0.999
3:132721967:A:G	L130P	0.999
3:132721979:A:G	L126P	0.999
3:132686290:C:T	G1100D	0.998
3:132686291:C:G	G1100R	0.998
3:132688744:C:G	A1011P	0.998
3:132688857:C:G	R973P	0.998
3:132701431:A:G	W543R	0.998
3:132701431:A:T	W543R	0.998
3:132719127:T:A	K179N	0.998
3:132719127:T:G	K179N	0.998
3:132719136:C:A	R176S	0.998
3:132719136:C:G	R176S	0.998
3:132719139:A:C	F175L	0.998
3:132719139:A:T	F175L	0.998
3:132719141:A:G	F175L	0.998
3:132721976:C:G	R127P	0.998
3:132682044:C:G	A1287P	0.997
3:132682712:G:T	A1268D	0.997
3:132682724:A:G	L1264P	0.997

dbSNP variants (sampled 300 via entrez): RS1000307539 (3:132721604 G>C,T), RS1000348001 (3:132690229 A>G), RS1000353417 (3:132683230 A>G), RS1000413166 (3:132686861 A>G), RS1000500789 (3:132701067 A>G), RS1000506277 (3:132712548 C>A), RS1000515512 (3:132702339 A>T), RS1000557306 (3:132709338 A>G), RS1000611201 (3:132709149 C>G), RS1000624307 (3:132708823 A>G), RS1000877717 (3:132692601 G>A,C), RS1000973579 (3:132696282 C>A,T), RS1001045384 (3:132696066 T>C), RS1001111750 (3:132699657 A>G), RS1001183652 (3:132705491 A>G)

Disease associations

OMIM: gene MIM:608002 | disease phenotypes: MIM:208540, MIM:267010, MIM:604387, MIM:256100, MIM:204000, MIM:209900, MIM:173900, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
nephronophthisis	Definitive	Autosomal recessive
nephronophthisis 3	Definitive	Autosomal recessive
Senior-Loken syndrome	Definitive	Autosomal recessive
renal-hepatic-pancreatic dysplasia	Supportive	Autosomal recessive
NPHP3-related Meckel-like syndrome	Supportive	Autosomal recessive
late-onset nephronophthisis	Supportive	Autosomal recessive
nephronophthisis 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nephronophthisis	Definitive	AR

Mondo (17): renal-hepatic-pancreatic dysplasia 1 (MONDO:0008833), NPHP3-related Meckel-like syndrome (MONDO:0009966), nephronophthisis 3 (MONDO:0011456), nephronophthisis (MONDO:0019005), inherited retinal dystrophy (MONDO:0019118), Leber congenital amaurosis (MONDO:0018998), Bardet-Biedl syndrome (MONDO:0015229), kidney disorder (MONDO:0005240), Joubert syndrome and related disorders (MONDO:0015369), polycystic kidney disease (MONDO:0020642), optic atrophy (MONDO:0003608), focal segmental glomerulosclerosis (MONDO:0100313), congenital anomaly of kidney and urinary tract (MONDO:0019719), renal-hepatic-pancreatic dysplasia (MONDO:0017417), Senior-Loken syndrome (MONDO:0017842)

Orphanet (7): NPHP3-related Meckel-like syndrome (Orphanet:3032), Nephronophthisis (Orphanet:655), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Leber congenital amaurosis (Orphanet:65), Bardet-Biedl syndrome (Orphanet:110), Joubert syndrome and related disorders (Orphanet:140874), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000083	Renal insufficiency
HP:0000090	Nephronophthisis
HP:0000092	Renal tubular atrophy
HP:0000093	Proteinuria
HP:0000103	Polyuria
HP:0000104	Renal agenesis
HP:0000105	Enlarged kidney
HP:0000107	Renal cyst
HP:0000108	Renal corticomedullary cysts
HP:0000110	Renal dysplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000239	Large fontanelles
HP:0000348	High forehead
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000556	Retinal dystrophy
HP:0000790	Hematuria
HP:0000805	Enuresis
HP:0000822	Hypertension
HP:0000952	Jaundice
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001305	Dandy-Walker malformation
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000880_27	Menarche (age at onset)	1.000000e-08
GCST003993_15	Menarche (age at onset)	4.000000e-06
GCST004602_131	Mean corpuscular volume	2.000000e-10
GCST004630_121	Mean corpuscular hemoglobin	3.000000e-14
GCST010699_54	Brain morphology (min-P)	5.000000e-08
GCST010701_80	Cortical surface area (MOSTest)	5.000000e-09
GCST010702_60	Subcortical volume (MOSTest)	6.000000e-12
GCST010703_12	Brain morphology (MOSTest)	9.000000e-10
GCST90011900_25	Serum alkaline phosphatase levels	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004527	mean corpuscular hemoglobin
EFO:0004346	neuroimaging measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D007690	Polycystic Kidney Diseases	C12.050.351.968.419.403.875; C12.200.777.419.403.875; C12.950.419.403.875; C16.131.077.717; C16.320.184.625
D058499	Retinal Dystrophies	C11.768.585.658
C566906	Cakut (supp.)
C566582	Nephronophthisis 2 (supp.)
C565780	Nephronophthisis 3 (supp.)
C537756	Renal hepatic pancreatic dysplasia Dandy Walker cyst (supp.)
C537580	Senior Loken Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Temozolomide	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Coumestrol	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Estradiol	decreases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Volatile Organic Compounds	increases oxidation, affects cotreatment	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D6A3	HyCyte HEK293T KO-hNPHP3	Transformed cell line	Female
CVCL_D6BQ	HyCyte HK-2 KO-hNPHP3	Transformed cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia
NCT03029351	PHASE4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes