UPK3A

protein-coding

uroplakin 3A

Gene summary

This gene encodes a member of the uroplakin family, a group of transmembrane proteins that form complexes on the apical surface of the bladder epithelium. Mutations in this gene may be associated with renal adysplasia. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

Previous symbols:

UPK3

MANE transcript

NM_006953.4

Inheritance

ClinVar variants

P:1U:65B:19

Top phenotype

Renal/urogenital adysplasia

gnomAD constraint

pLI —, LoF o/e 1.19

Max pathogenic AF

—

Genomic locus

chr22:45,284,949-45,295,874

External References & Databases

Ensembl (ENSG00000100373)

Transcript & Mutation Effects

hg38 • Region Span ~10.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal agenesis, unilateralSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019636

Submitter: Orphanet

renal dysplasiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019638

Submitter: Ambry Genetics

congenital anomaly of kidney and urinary tractNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0019719

Submitter: ClinGen

UPK3A was first reported in relation to autosomal dominant Congenital anomaly of the kidney and urinary tract (CAKUT) in 2005 (Jenkins et al., PMID: 15888565). At the time of curation, there were no single gene disorders associated with UPK3A. In the literature, UPK3A was implicated in the pathogenesis of CAKUT, Renal agenesis/Hypoplasia, and Vesicoureteral reflux (VUR). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference/difference in molecular mechanism and inheritance pattern, with CAKUT, VUR, and Renal agenesis/hypoplasia being representative of a CAKUT phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity, CAKUT (MONDO:0019719).8 variants (missense, nonsense, frameshift) that have been reported in 9 probands in publications (PMIDs:16731295 ,22558067, 26489027, 30773290, 32164334, 34979951, 36417404) are included in this curation. The majority of these variants were scored at 0 points due to all high frequencies in populations. This gene-disease association is also supported by an animal model and expression studies. In summary, the evidence supporting the relationship between UPK3A and autosomal dominant Congenital anomaly of the kidney and urinary tract has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role. This classification was approved by the ClinGen CAKUT GCEP on the meeting date 1/9/23 (SOP Version 9).

Clinical Genomic Database (CGD)

Renal/urogenital adysplasiaAD

Manifestation: Genitourinary; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The condition has been described as involving progressive, inexorable renal failure, and renal transplant has been described

Refs: 15888565

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UPK3A variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 49

Renal hypodysplasia/aplasia 1Total: 28

not providedTotal: 19

UPK3A-related disorderTotal: 14

Congenital anomalies of kidney and urinary tract 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006953.4. 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			5 clinvar	6 clinvar	1 clinvar	12
missense			57 clinvar	8 clinvar	1 clinvar	66
nonsense			1 clinvar	2 clinvar		3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar	1 clinvar		4
Total	0	1	65	17	2	85

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006953.4	RefSeq	NP_008884.1	6	MANE Select
ENST00000216211.9	Ensembl	ENSP00000216211.4	6	MANE Select
NM_001167574.2	RefSeq	NP_001161046.1	4	Standard
ENST00000396082.2	Ensembl	ENSP00000379391.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Bladder cancer - Homo sapiens (human)

Biological Process

cell morphogenesis
kidney development
water transport
urea transport
epithelial cell differentiation

Molecular Function

protein binding

Cellular Component

endoplasmic reticulum membrane
extracellular exosome
apical plasma membrane urothelial plaque

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216211
Coding exons: 6
Length: 10893
Individuals with no LoFs: 123504
Homozygous LoFs: 20
Heterozygous LoFs: 2224
Defined: 125748
p: 0.00896

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.411	180	165	1.09	0.00000977	1816
Missense (PolyPhen)		67	51.783	1.2939		647
Synonymous	0.563	70	76.3	0.918	0.00000515	619
Loss of Function	-0.610	14	11.7	1.19	6.07e-7	124

Population LoF Frequency

Population	CAF	p-value	Status
African	0.032	0.032	notable
Latino/Admixed American	0.010	0.010	notable
Ashkenazi Jewish	0.0033	0.0033	notable
East Asian	0.027	0.027	notable
Finnish	0.027	0.027	notable
European (Non-Finnish)	0.0019	0.0018	notable
South Asian	0.0012	0.0011	notable
Other	0.0070	0.0069	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in AUM-cytoskeleton interaction in terminally differentiated urothelial cells. It also contributes to the formation of urothelial glycocalyx which may play an important role in preventing bacterial adherence (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.0995

Intolerance Scores

LoFtool: 0.572
RVIS EVS: 0.89
RVIS percentile EVS: 89.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.930

Gene Damage Prediction

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