NHERF1

protein-coding

NHERF family PDZ scaffold protein 1, the group of MicroRNA protein coding host genes|PDZ domain containing|NHERF family PDZ scaffold proteins

Gene summary

This gene encodes a sodium/hydrogen exchanger regulatory cofactor. The protein interacts with and regulates various proteins including the cystic fibrosis transmembrane conductance regulator and G-protein coupled receptors such as the beta2-adrenergic receptor and the parathyroid hormone 1 receptor. The protein also interacts with proteins that function as linkers between integral membrane and cytoskeletal proteins. The protein localizes to actin-rich structures including membrane ruffles, microvilli, and filopodia. Mutations in this gene result in hypophosphatemic nephrolithiasis/osteoporosis type 2, and loss of heterozygosity of this gene is implicated in breast cancer.[provided by RefSeq, Sep 2009]

Previous symbols:

SLC9A3R1

MANE transcript

NM_004252.5

Inheritance

ClinVar variants

U:129B:56

Top phenotype

Nephrolithiasis/osteoporosis, hypophosphatemic, 2

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr17:74,748,628-74,769,353

External References & Databases

Ensembl (ENSG00000109062)

Transcript & Mutation Effects

hg38 • Region Span ~20.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypophosphatemic nephrolithiasis/osteoporosis 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012851

Submitter: PanelApp Australia

hypophosphatemic nephrolithiasis/osteoporosis 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012851

Submitter: Ambry Genetics

dominant hypophosphatemia with nephrolithiasis or osteoporosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016579

Submitter: Orphanet

hypophosphatemic nephrolithiasis/osteoporosis 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012851

Submitter: Labcorp Genetics (formerly Invitae)

hypophosphatemic nephrolithiasis/osteoporosis 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012851

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Nephrolithiasis/osteoporosis, hypophosphatemic, 2AD

Manifestation: Renal

Intervention: Renal

Rationale: Due to increased renal phosphate loss, individuals may be at increased risk of renal stone formation and/or bone demineralization, and preventive measures may be beneficial

Refs: 18784102

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHERF1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 151

Inborn genetic diseasesTotal: 76

NHERF1-related disorderTotal: 24

Hypophosphatemic nephrolithiasis/osteoporosis 2Total: 16

not specifiedTotal: 13

Dominant hypophosphatemia with nephrolithiasis or osteoporosisTotal: 5

Kidney stoneTotal: 1

Chronic kidney diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004252.5. 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			2 clinvar	40 clinvar		42
missense			118 clinvar	15 clinvar		133
nonsense			3 clinvar			3
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			4 clinvar	1 clinvar		5
Total	0	0	129	56	0	185

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004252.5	RefSeq	NP_004243.1	6	MANE Select
ENST00000262613.10	Ensembl	ENSP00000262613.5	6	MANE Select
ENST00000413388.2	Ensembl	ENSP00000464982.1	5	Standard
ENST00000413388.3	Ensembl	ENSP00000464982.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc9a3r1a	Danio rerio	Structure: ventricular system Quality: hydrocephalic abnormal

Gene / Model

Organism

Observed Phenotype

slc9a3r1a

Danio rerio

Structure: ventricular system

Quality: hydrocephalic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
Beta-agonist/Beta-blocker Pathway, Pharmacodynamics
cystic fibrosis transmembrane conductance regulator (cftr) and beta 2 adrenergic receptor (b2ar) pathway
Thromboxane A2 receptor signaling

Biological Process

renal sodium ion transport
nuclear migration
adenylate cyclase-activating dopamine receptor signaling pathway
sensory perception of sound
negative regulation of cell population proliferation

Molecular Function

signaling receptor binding
protein binding
beta-catenin binding
chloride channel regulator activity
phosphatase binding

Cellular Component

ruffle
nucleus
cytoplasm
microvillus
endomembrane system

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262613
Coding exons: 6
Length: 20702
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 92
Defined: 125745
p: 0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.472	231	212	1.09	0.0000121	2301
Missense (PolyPhen)		91	94.808	0.95983		975
Synonymous	-0.589	103	95.7	1.08	0.00000584	737
Loss of Function	1.17	8	12.5	0.641	5.43e-7	153

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.00026	0.00026	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules. Involved in sperm capacitation. May participate in the regulation of the chloride and bicarbonate homeostasis in spermatozoa. {ECO:0000250, ECO:0000269|PubMed:10499588, ECO:0000269|PubMed:18784102, ECO:0000269|PubMed:9096337, ECO:0000269|PubMed:9430655}.;
Disease: DISEASE: Nephrolithiasis/osteoporosis, hypophosphatemic, 2 (NPHLOP2) [MIM:612287]: A disease characterized by decreased renal phosphate absorption, renal phosphate wasting, hypophosphatemia, hyperphosphaturia, hypercalciuria, nephrolithiasis and osteoporosis. {ECO:0000269|PubMed:18784102, ECO:0000269|PubMed:22506049}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.498

Intolerance Scores

LoFtool: 0.837
RVIS EVS: 0.31
RVIS percentile EVS: 72.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.957

Gene Damage Prediction

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