NHERF1

Chr 17ARAD

NHERF family PDZ scaffold protein 1

Also known as: EBP50, NHE-RF, NHERF, NHERF-1, NPHLOP2, SLC9A3R1

NCBI Gene: 9368 ENSG00000109062 UniProt: O14745

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]

Primary Disease Associations & Inheritance

Diarrhea 8, secretory sodium, congenitalMIM #616868

Nephrolithiasis/osteoporosis, hypophosphatemic, 2MIM #612287

{Glioma susceptibility 2}MIM #613028

{Meningioma}MIM #607174

Cowden syndrome 1MIM #158350

Lhermitte-Duclos diseaseMIM #158350

Macrocephaly/autism syndromeMIM #605309

Prostate cancer, somaticMIM #176807

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

-0.5

Missense Z

1.16

LOEUF

Clinical Summary— NHERF1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.16LOEUF

pLI 0.000

Z-score 1.17

OE 0.64 (0.38–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.47Z-score

OE missense 1.09 (0.98–1.22)

231 obs / 211.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.64 (0.38–1.16)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.09 (0.98–1.22)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08

0≤1.21.6

LoF obs/exp: 8 / 12.5Missense obs/exp: 231 / 211.7Syn Z: -0.59

0.7033th %ile

GOF

0.74top 25%

LOF

0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.