NPHP3

protein-coding

nephrocystin 3, the group of Cilia and flagella associated|Tetratricopeptide repeat domain containing

Gene summary

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. [provided by RefSeq, Feb 2011]

MANE transcript

NM_153240.5

Inheritance

ClinVar variants

P:188U:644B:284

Top phenotype

Nephronophthisis 3; Meckel syndrome, type 7; Renal-hepatic-pancreatic dysplasia 1

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr3:132,680,609-132,722,432

External References & Databases

Ensembl (ENSG00000113971)

Transcript & Mutation Effects

hg38 • Region Span ~41.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Natera

nephronophthisis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011456

Submitter: Labcorp Genetics (formerly Invitae)

NPHP3-related Meckel-like syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009966

Submitter: Orphanet

renal-hepatic-pancreatic dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017417

Submitter: Orphanet

nephronophthisis 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Orphanet

nephronophthisisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019005

Submitter: PanelApp Australia

nephronophthisisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019005

Submitter: ClinGen

*NPHP3 *was first reported in relation to autosomal recessive nephronophthisis in 2003 (Olbrich et al., PMID: 12872122), after direction by linkage analysis and homozygosity mapping by Omran et al in 2000 (PMID: 10631142). There are a number of different disease entities described as associated with *NPHP3 *in OMIM, including nephronophthisis, renal-hepatic-pancreatic-dysplasia and Meckel syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism OR inheritance pattern between these different disease entities. Therefore, these disease entities have been lumped into one disease which we suggest is referred to as ‘nephronophthisis – *NPHP3*’. Multiple variants (missense, in-frame, indel and predicted protein truncating variants) have been reported across multiple probands in multiple publications (PMIDs: 12872122, 19177160) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies and animal models (mice and zebrafish) (PMIDs: 12872122, 18371931, 20462968). In summary, *NPHP3 *is strongly associated with autosomal recessive nephronophthisis (NPHP-*NPHP3*). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP on 07/24/2021 (SOP Version 8).

Senior-Loken syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017842

Submitter: G2P

Senior-Loken syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017842

Submitter: Orphanet

nephronophthisis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011456

Submitter: G2P

late-onset nephronophthisisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019742

Submitter: Orphanet

Clinical Genomic Database (CGD)

Nephronophthisis 3; Meckel syndrome, type 7; Renal-hepatic-pancreatic dysplasia 1AR

Manifestation: Gastrointestinal; Hematologic; Musculoskeletal; Renal

Intervention: General

Rationale: 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

Comments: Liver-kidney transplantation has been described

Refs: 8874114; 12872122; 18371931; 19303681; 19177160; 20007846; 21068128; 21642631;21866095

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NPHP3 variants in ClinVar

29 Conditions Cataloged

NephronophthisisTotal: 982

Nephronophthisis 3Total: 380

Renal-hepatic-pancreatic dysplasia 1Total: 365

NPHP3-related Meckel-like syndromeTotal: 363

not providedTotal: 357

NPHP3-related disorderTotal: 240

not specifiedTotal: 156

Inborn genetic diseasesTotal: 134

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153240.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	15 clinvar	251 clinvar	4 clinvar	271
missense	1 clinvar	17 clinvar	620 clinvar	27 clinvar	2 clinvar	667
nonsense	37 clinvar	21 clinvar	1 clinvar			59
start loss		2 clinvar	1 clinvar			3
frameshift	36 clinvar	42 clinvar	3 clinvar			81
splice donor/acceptor (+/-2bp)	6 clinvar	25 clinvar	4 clinvar			35
Total	80	108	644	278	6	1116

Highest pathogenic variant AF is 0.00023482004

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153240.5	RefSeq	NP_694972.3	27	MANE Select
ENST00000337331.10	Ensembl	ENSP00000338766.5	27	MANE Select
ENST00000383282.3	Ensembl	ENSP00000372769.2	2	Standard
ENST00000383282.4	Ensembl	ENSP00000372769.2	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nphp3	Danio rerio	Structure: trunk Quality: curved ventral abnormal

Gene / Model

Organism

Observed Phenotype

nphp3

Danio rerio

Structure: trunk

Quality: curved ventral

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Trafficking of myristoylated proteins to the cilium
Cargo trafficking to the periciliary membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

kidney development
heart looping
atrial septum development
determination of left/right symmetry
Wnt signaling pathway

Molecular Function

protein binding

Cellular Component

cytosol
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337331
Coding exons: 27
Length: 164318
Individuals with no LoFs: 125511
Homozygous LoFs: 0
Heterozygous LoFs: 237
Defined: 125748
p: 0.000943

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.864	627	691	0.908	0.0000352	8672
Missense (PolyPhen)		179	205.57	0.87075		2578
Synonymous	1.41	228	257	0.888	0.0000129	2522
Loss of Function	4.10	38	76.7	0.495	0.00000398	923

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00090	0.00090	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0016	0.0016	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0012	0.0012	notable
South Asian	0.00075	0.00075	rare
Other	0.00099	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:18371931}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:18371931}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:18371931}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.196

Intolerance Scores

LoFtool: 0.153
RVIS EVS: -1.01
RVIS percentile EVS: 8.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.747

Gene Damage Prediction

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