NHERF1

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

Basic information

Region (hg38): 17:74748628-74769353

Previous symbols: [ "SLC9A3R1" ]

Links

ENSG00000109062 ∙ NCBI:9368 ∙ OMIM:604990 ∙ HGNC:11075 ∙ Uniprot:O14745 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypophosphatemic nephrolithiasis/osteoporosis 2 (Limited), mode of inheritance: Unknown
• dominant hypophosphatemia with nephrolithiasis or osteoporosis (Supportive), mode of inheritance: AD
• hypophosphatemic nephrolithiasis/osteoporosis 2 (Moderate), mode of inheritance: AD
• hypophosphatemic nephrolithiasis/osteoporosis 2 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Nephrolithiasis/osteoporosis, hypophosphatemic, 2	AD	Renal	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	Renal	18784102

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NHERF1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NHERF1 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	3	28
missense			62	9		71
nonsense			2			2
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1	3	1	5
non coding			2	8	7	17
Total	0	0	67	42	10

Variants in NHERF1

This is a list of pathogenic ClinVar variants found in the NHERF1 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-74748659-G-C			Benign (Oct 16, 2018)
17-74748731-C-T			Likely benign (May 25, 2021)
17-74748772-G-A			Likely benign (Sep 23, 2019)
17-74748804-C-A			Likely benign (Jul 17, 2019)
17-74748851-G-A			Uncertain significance (Jan 15, 2024)
17-74748854-C-T			Uncertain significance (Apr 05, 2022)
17-74748872-C-A		NHERF1-related disorder	Uncertain significance (Jan 10, 2023)
17-74748879-G-T			Uncertain significance (-)
17-74748890-G-T			Uncertain significance (Apr 08, 2021)
17-74748914-G-T		Inborn genetic diseases	Uncertain significance (Feb 02, 2024)
17-74748917-A-G			Uncertain significance (Oct 01, 2023)
17-74748927-C-G		Inborn genetic diseases	Uncertain significance (Jul 20, 2021)
17-74748931-C-A		Hypophosphatemic nephrolithiasis/osteoporosis 2 • Inborn genetic diseases • NHERF1-related disorder	Conflicting classifications of pathogenicity (Mar 20, 2024)
17-74748935-G-A			Uncertain significance (-)
17-74748948-G-C			Uncertain significance (Oct 25, 2023)
17-74748953-G-A		Hypophosphatemic nephrolithiasis/osteoporosis 2	Uncertain significance (Mar 08, 2024)
17-74748966-G-T			Likely benign (Apr 16, 2023)
17-74748968-T-A			Uncertain significance (Nov 24, 2022)
17-74748976-C-G			Likely benign (May 28, 2023)
17-74748978-C-T		NHERF1-related disorder	Benign (Oct 14, 2023)
17-74748983-C-T		Inborn genetic diseases	Uncertain significance (Aug 12, 2022)
17-74748996-G-A			Likely benign (Mar 14, 2023)
17-74749000-G-A		Inborn genetic diseases	Uncertain significance (Jun 29, 2023)
17-74749011-G-C			Likely benign (Jan 04, 2024)
17-74749046-TGGA-T			Uncertain significance (Sep 16, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NHERF1	protein_coding	protein_coding	ENST00000262613	6	20702

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000884	0.796	125653	0	92	125745	0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.472	231	212	1.09	0.0000121	2301
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000568	0.000557
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.000515	0.000510
Middle Eastern	0.000272	0.000272
South Asian	0.000265	0.000261
Other	0.000490	0.000489

dbNSFP

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.
• Pathway: 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;PDGFR-beta signaling pathway (Consensus)

Recessive Scores

• pRec: 0.498

Intolerance Scores

• loftool: 0.837
• rvis_EVS: 0.31
• rvis_percentile_EVS: 72.38

Haploinsufficiency Scores

• pHI: 0.182
• hipred: Y
• hipred_score: 0.550
• ghis: 0.399

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.957

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Slc9a3r1
• 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); digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: slc9a3r1a
• Affected structure: ventricular system
• Phenotype tag: abnormal
• Phenotype quality: hydrocephalic

Gene ontology

• 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;regulation of cell shape;regulation of cell size;negative regulation of platelet-derived growth factor receptor signaling pathway;negative regulation of phosphatidylinositol 3-kinase signaling;Wnt signaling pathway;gland morphogenesis;microvillus assembly;actin cytoskeleton organization;negative regulation of cell migration;cellular phosphate ion homeostasis;regulation of sodium:proton antiporter activity;negative regulation of sodium:proton antiporter activity;bile acid secretion;glutathione transport;positive regulation of ion transmembrane transport;regulation of excretion;establishment of epithelial cell apical/basal polarity;regulation of protein kinase activity;negative regulation of mitotic cell cycle;establishment of Golgi localization;negative regulation of protein kinase B signaling;auditory receptor cell stereocilium organization;phospholipase C-activating dopamine receptor signaling pathway;protein-containing complex assembly;renal absorption;negative regulation of ERK1 and ERK2 cascade;protein localization to plasma membrane;negative regulation of canonical Wnt signaling pathway;renal phosphate ion absorption;positive regulation of intrinsic apoptotic signaling pathway
• Cellular component: ruffle;nucleus;cytoplasm;microvillus;endomembrane system;actin cytoskeleton;membrane;apical plasma membrane;filopodium;brush border membrane;microvillus membrane;vesicle;stereocilium tip;membrane raft;perinuclear region of cytoplasm;extracellular exosome;cell periphery;sperm midpiece
• Molecular function: signaling receptor binding;protein binding;beta-catenin binding;chloride channel regulator activity;phosphatase binding;PDZ domain binding;beta-2 adrenergic receptor binding;protein-containing complex scaffold activity;protein self-association;protein-containing complex binding;myosin II binding;protein N-terminus binding;dopamine receptor binding;growth factor receptor binding