NHERF4

Chr 11

NHERF family PDZ scaffold protein 4

Also known as: IKEPP, PDZD3, PDZK2

NCBI Gene: 79849 ENSG00000172367 UniProt: Q86UT5 OMIM: 607146

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]

OMIM Research

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.27

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.27LOEUF

pLI 0.000

Z-score 0.57

OE 0.87 (0.61–1.27)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.42Z-score

OE missense 0.93 (0.84–1.03)

271 obs / 291.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.87 (0.61–1.27)

0≤0.351.4

Missense OE?0.93 (0.84–1.03)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 20 / 22.9Missense obs/exp: 271 / 291.3Syn Z: 0.88

Background carrier burden — how many people carry a rare variant somewhere in NHERF4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 50

792 rare PASS variants

Rare truncating (LoF)

1 in 320

173 rare PASS variants

Rare synonymous (reference)

1 in 210

346 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NHERF4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 70	1 in 360
South Asian	~43k	1 in 57	1 in 400
Remaining (unassigned)	~30k	1 in 41	1 in 220
European (Finnish)	~27k	1 in 110	1 in 1,200
Admixed American	~22k	1 in 62	1 in 390
African / African American	~21k	1 in 61	1 in 600
East Asian	~20k	1 in 74	1 in 240
Ashkenazi Jewish	~13k	1 in 140	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 70	1 in 290

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓