PDZRN3

Chr 3

PDZ domain containing ring finger 3

Also known as: LNX3, SEMACAP3, SEMCAP3

NCBI Gene: 23024 ENSG00000121440 UniProt: Q9UPQ7 OMIM: 609729

This gene encodes a RING-type E3 ubiquitin ligase that regulates muscle-specific kinase (MUSK) levels on muscle cells by mediating its ubiquitination and degradation, contributing to terminal muscle differentiation. Mutations cause autosomal recessive congenital myasthenic syndrome, a neuromuscular junction disorder presenting in infancy or early childhood with muscle weakness, fatigue, and respiratory difficulties. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the LNX (Ligand of Numb Protein-X) family of RING-type ubiquitin E3 ligases. This protein may function in vascular morphogenesis and the differentiation of adipocytes, osteoblasts and myoblasts. This protein may be targeted for degradation by the human papilloma virus E6 protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.30

Clinical Summary— PDZRN3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

85 VUS of 98 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.985

Z-score 4.68

OE 0.14 (0.07–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.94–1.07)

623 obs / 622.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.30)

0≤0.351.4

Missense OE?1.00 (0.94–1.07)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 34.7Missense obs/exp: 623 / 622.6Syn Z: -2.02

This gene — mechanism propensity

0.4289th %ile

GOF

0.5269th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.30

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

98 submitted variants in ClinVar

ClinVar

Classification Summary

VUS85

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	85	85
Likely Benign	1	1
Benign	0	0
Total	86	86

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

1 pathogenic / likely-pathogenic (of 2) ClinVar copy-number / structural variants overlap PDZRN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →