USP44

protein-coding

ubiquitin specific peptidase 44, the group of Ubiquitin specific peptidases

Gene summary

The protein encoded by this gene is a protease that functions as a deubiquitinating enzyme. The encoded protein is thought to help regulate the spindle assembly checkpoint by preventing early anaphase onset. This protein specifically deubiquitinates CDC20, which stabilizes the anaphase promoting complex/cyclosome. [provided by RefSeq, Dec 2016]

MANE transcript

NM_032147.5

Inheritance

ClinVar variants

U:86B:13

Top phenotype

USP44-related disorder

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr12:95,516,560-95,551,476

External References & Databases

Ensembl (ENSG00000136014)

Transcript & Mutation Effects

hg38 • Region Span ~34.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

USP44 was first reported in relation to autosomal dominant congenital heart disease in 2020 (Edwards et al., PMID: 32368696). 4 variants (missense, nonsense, frameshift) that have been reported in 4 probands in 2 publications (PMIDs: 32368696, 33084842) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (NCBI fetal expression-level data, fish embryo model). Expression-level data from NCBI shows solid expression in the heart at 10 weeks gestation. Gene-editing of USP44 in fish embryos resulted in abnormal heart morphology and looping defects. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 10/15/24 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP44 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 86

not providedTotal: 6

USP44-related disorderTotal: 6

Moderate intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032147.5. 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	2 clinvar	6
missense			85 clinvar	4 clinvar	3 clinvar	92
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	86	8	5	99

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 108 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032147.5	RefSeq	NP_115523.2	5	MANE Select
ENST00000258499.8	Ensembl	ENSP00000258499.3	5	MANE Select
NM_001042403.3	RefSeq	NP_001035862.1	5	Standard
NM_001278393.2	RefSeq	NP_001265322.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
usp44	Danio rerio	Structure: pharyngeal arch cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

usp44

Danio rerio

Structure: pharyngeal arch cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Ub-specific processing proteases
Deubiquitination

Biological Process

cell cycle
protein deubiquitination
proteasome-mediated ubiquitin-dependent protein catabolic process
cell division
regulation of mitotic cell cycle spindle assembly checkpoint

Molecular Function

thiol-dependent ubiquitin-specific protease activity
protein binding
zinc ion binding
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258499
Coding exons: 5
Length: 34931
Individuals with no LoFs: 125608
Homozygous LoFs: 1
Heterozygous LoFs: 139
Defined: 125748
p: 0.000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.654	348	384	0.906	0.0000200	4671
Missense (PolyPhen)		101	116.33	0.86823		1459
Synonymous	0.745	126	137	0.919	0.00000725	1348
Loss of Function	1.23	26	33.7	0.772	0.00000204	382

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.00076	0.00072	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00049	0.00049	rare
Finnish	0.000050	0.000046	rare
European (Non-Finnish)	0.00058	0.00056	rare
South Asian	0.00026	0.00026	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinase that plays a key regulatory role in the spindle assembly checkpoint or mitotic checkpoint by preventing premature anaphase onset. Acts by specifically mediating deubiquitination of CDC20, a negative regulator of the anaphase promoting complex/cyclosome (APC/C). Deubiquitination of CDC20 leads to stabilize the MAD2L1-CDC20-APC/C ternary complex (also named mitotic checkpoint complex), thereby preventing premature activation of the APC/C. Promotes association of MAD2L1 with CDC20 and reinforces the spindle assembly checkpoint. Acts as a negative regulator of histone H2B (H2BK120ub1) ubiquitination. {ECO:0000269|PubMed:17443180, ECO:0000269|PubMed:22681888}.;

Recessive Scores

pRec: 0.0872

Intolerance Scores

LoFtool: 0.988
RVIS EVS: -0.29
RVIS percentile EVS: 33.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.193

Gene Damage Prediction

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