UPB1

protein-coding

beta-ureidopropionase 1

Gene summary

This gene encodes a protein that belongs to the CN hydrolase family. Beta-ureidopropionase catalyzes the last step in the pyrimidine degradation pathway. The pyrimidine bases uracil and thymine are degraded via the consecutive action of dihydropyrimidine dehydrogenase (DHPDH), dihydropyrimidinase (DHP) and beta-ureidopropionase (UP) to beta-alanine and beta-aminoisobutyric acid, respectively. UP deficiencies are associated with N-carbamyl-beta-amino aciduria and may lead to abnormalities in neurological activity. [provided by RefSeq, Jul 2008]

MANE transcript

NM_016327.3

Inheritance

ClinVar variants

P:22U:105B:62

Top phenotype

Beta-ureidopropionase deficiency

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr22:24,494,107-24,528,390

External References & Databases

Ensembl (ENSG00000100024)

Transcript & Mutation Effects

hg38 • Region Span ~34.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

beta-ureidopropionase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013164

Submitter: Orphanet

beta-ureidopropionase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013164

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

beta-ureidopropionase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013164

Submitter: Labcorp Genetics (formerly Invitae)

beta-ureidopropionase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013164

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Beta-ureidopropionase deficiencyAR

Manifestation: Biochemical; Neurologic

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: As with many disorders involving seizure risk, optimal control is beneficial; Normal neurologic development has been described (in addition to severe neurologic manifestations)

Refs: 15385443; 17964839; 22525402; 35151535

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UPB1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 162

Deficiency of beta-ureidopropionaseTotal: 60

Inborn genetic diseasesTotal: 59

UPB1-related disorderTotal: 8

not specifiedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016327.3. 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			4 clinvar	47 clinvar	5 clinvar	56
missense		4 clinvar	97 clinvar	10 clinvar		111
nonsense	4 clinvar	1 clinvar	1 clinvar			6
start loss						0
frameshift	6 clinvar	3 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	1 clinvar			5
Total	11	11	105	57	5	189

Highest pathogenic variant AF is 0.0018944369

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 77 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016327.3	RefSeq	NP_057411.1	10	MANE Select
ENST00000326010.10	Ensembl	ENSP00000324343.5	10	MANE Select
ENST00000382760.2	Ensembl	ENSP00000372208.2	4	Standard
ENST00000382760.3	Ensembl	ENSP00000372208.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
beta-Alanine metabolism - Homo sapiens (human)
Pantothenate and CoA biosynthesis - Homo sapiens (human)
Drug metabolism - other enzymes - Homo sapiens (human)
Fluoropyrimidine Pathway, Pharmacokinetics

Biological Process

beta-alanine metabolic process
beta-alanine biosynthetic process via 3-ureidopropionate
pyrimidine nucleoside catabolic process

Molecular Function

beta-ureidopropionase activity
metal ion binding

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326010
Coding exons: 10
Length: 61153
Individuals with no LoFs: 125018
Homozygous LoFs: 2
Heterozygous LoFs: 728
Defined: 125748
p: 0.00291

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.866	261	224	1.16	0.0000145	2512
Missense (PolyPhen)		101	83.604	1.2081		908
Synonymous	-1.42	110	92.6	1.19	0.00000691	739
Loss of Function	0.630	19	22.2	0.856	0.00000134	233

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.0032	0.0032	notable
Ashkenazi Jewish	0.0049	0.0049	notable
East Asian	0.00038	0.00038	rare
Finnish	0.0018	0.0018	notable
European (Non-Finnish)	0.0033	0.0033	notable
South Asian	0.0032	0.0032	notable
Other	0.0055	0.0056	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Converts N-carbamoyl-beta-aminoisobutyrate and N- carbamoyl-beta-alanine (3-ureidopropanoate) to, respectively, beta-aminoisobutyrate and beta-alanine, ammonia and carbon dioxide.;
Disease: DISEASE: Beta-ureidopropionase deficiency (UPB1D) [MIM:613161]: An inborn error of metabolism due to a defect in pyrimidine degradation. It is characterized by muscular hypotonia, dystonic movements, scoliosis, microcephaly and severe developmental delay. Patients show strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. {ECO:0000269|PubMed:15385443}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.190

Intolerance Scores

LoFtool: 0.281
RVIS EVS: -0.69
RVIS percentile EVS: 15.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.867

Gene Damage Prediction

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