NHERF4

protein-coding

NHERF family PDZ scaffold protein 4, the group of PDZ domain containing|NHERF family PDZ scaffold proteins

Gene summary

Guanylyl cyclase C (GCC, or GUCY2C; MIM 601330) produces cGMP following the binding of either endogenous ligands or heat-stable enterotoxins secreted by E. coli and other enteric bacteria. Activation of GCC initiates a signaling cascade that leads to phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR; MIM 602421), followed by a net efflux of ions and water into the intestinal lumen. IKEPP is a regulatory protein that associates with GCC and regulates the amount of cGMP produced following receptor stimulation (Scott et al., 2002 [PubMed 11950846]).[supplied by OMIM, Mar 2008]

Previous symbols:

PDZK2
PDZD3

MANE transcript

NM_001168468.2

Inheritance

—

ClinVar variants

U:96B:6

Top phenotype

Congenital portosystemic shunt

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr11:119,185,457-119,190,223

External References & Databases

Ensembl (ENSG00000172367)

Transcript & Mutation Effects

hg38 • Region Span ~4.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHERF4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 98

Congenital portosystemic shuntTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001168468.2. 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			1
missense			94 clinvar	6 clinvar		100
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	96	6	0	102

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001168468.2	RefSeq	NP_001161940.1	11	MANE Select
ENST00000355547.10	Ensembl	ENSP00000347742.5	11	MANE Select
NM_024791.4	RefSeq	NP_079067.3	11	Standard
ENST00000322712.4	Ensembl	ENSP00000327107.4	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Disease
Intestinal infectious diseases
Uptake and actions of bacterial toxins
Infectious disease

Biological Process

ion transport
water transport
receptor guanylyl cyclase signaling pathway
response to toxic substance
negative regulation of cGMP-mediated signaling

Molecular Function

protein binding
protein C-terminus binding
ion channel inhibitor activity
guanylate cyclase inhibitor activity
ubiquitin-specific protease binding

Cellular Component

cytosol
brush border
subapical complex
apical part of cell

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355547
Coding exons: 11
Length: 4767
Individuals with no LoFs: 125569
Homozygous LoFs: 0
Heterozygous LoFs: 179
Defined: 125748
p: 0.000712

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.422	271	291	0.930	0.0000175	3163
Missense (PolyPhen)		77	91.594	0.84067		989
Synonymous	0.879	109	121	0.898	0.00000689	1103
Loss of Function	0.570	20	22.9	0.872	0.00000125	257

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0017	0.0017	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0010	0.0010	notable
South Asian	0.00027	0.00026	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation (PubMed:11950846). Stimulates SLC9A3 activity in the presence of elevated calcium ions (PubMed:19088451). {ECO:0000269|PubMed:11950846, ECO:0000269|PubMed:19088451}.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.983
RVIS EVS: -0.04
RVIS percentile EVS: 50.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.715

Gene Damage Prediction

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