UFSP2

protein-coding

UFM1 specific peptidase 2

Gene summary

This gene encodes a highly conserved cysteine protease. The protein cleaves two C-terminal residues from ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein. Activation of ubiquitin-fold modifier 1 by the encoded protein exposes a C-terminal glycine residue that allows interaction with other proteins and transfer to its target protein. An allelic variant of this gene has been associated with Beukes hip dysplasia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

Previous symbols:

C4orf20

MANE transcript

NM_018359.5

Inheritance

AD, AR

ClinVar variants

P:10U:77B:18

Top phenotype

Hip dysplasia, Beukes type; Spondyloepimetaphyseal dysplasia, Di Rocco type

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr4:185,399,537-185,425,979

External References & Databases

Ensembl (ENSG00000109775)

Transcript & Mutation Effects

hg38 • Region Span ~26.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hip dysplasia, Beukes typeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007726

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, di rocco typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060702

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 106LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0031052

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 106STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031052

Submitter: PanelApp Australia

hip dysplasia, Beukes typeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007726

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 106LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0031052

Submitter: G2P

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

hip dysplasia, Beukes typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007726

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hip dysplasia, Beukes type; Spondyloepimetaphyseal dysplasia, Di Rocco typeAD

Manifestation: Musculoskeletal

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

Refs: 2389793; 28892125

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UFSP2 variants in ClinVar

18 Conditions Cataloged

not specifiedTotal: 67

not providedTotal: 21

Hip dysplasia, Beukes typeTotal: 7

Spondyloepimetaphyseal dysplasia, di rocco typeTotal: 6

UFSP2-related disorderTotal: 5

Developmental and epileptic encephalopathy 106Total: 5

UFSP2-related neurodevelopmental disorderTotal: 1

Epileptic encephalopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018359.5. 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			2 clinvar	8 clinvar	4 clinvar	14
missense	4 clinvar	4 clinvar	69 clinvar	6 clinvar		83
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar	1 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	5	5	77	14	4	105

Highest pathogenic variant AF is 0.000071314826

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018359.5	RefSeq	NP_060829.2	12	MANE Select
ENST00000264689.11	Ensembl	ENSP00000264689.6	12	MANE Select
ENST00000502428.5	Ensembl	ENSP00000424419.1	5	Standard
ENST00000505357.1	Ensembl	ENSP00000423108.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

proteolysis
regulation of intracellular estrogen receptor signaling pathway

Molecular Function

protein binding
thiolester hydrolase activity
UFM1 hydrolase activity

Cellular Component

nucleus
cytoplasm
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264689
Coding exons: 12
Length: 26446
Individuals with no LoFs: 125686
Homozygous LoFs: 0
Heterozygous LoFs: 62
Defined: 125748
p: 0.000247

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.476	235	256	0.916	0.0000131	3070
Missense (PolyPhen)		58	80.236	0.72287		923
Synonymous	-0.124	93	91.5	1.02	0.00000501	884
Loss of Function	2.22	13	25.0	0.521	0.00000112	322

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00087	0.00086	rare
Latino/Admixed American	0.00025	0.00023	rare
Ashkenazi Jewish	0.00021	0.00020	rare
East Asian	0.00029	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00014	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Thiol protease which recognizes and hydrolyzes the peptide bond at the C-terminal Gly of UFM1, a ubiquitin-like modifier protein bound to a number of target proteins. Does not hydrolyze SUMO1 or ISG15 ubiquitin-like proteins. Through TRIP4 deufmylation may regulate intracellular nuclear receptors transactivation and thereby regulate cell proliferation and differentiation. {ECO:0000269|PubMed:25219498}.;
Disease: DISEASE: Beukes familial hip dysplasia (BFHD) [MIM:142669]: A severe progressive degenerative osteoarthritis of the hip joint with underlying dysplasia confined to that region. Affected individuals are of normal stature and have no associated health problems. {ECO:0000269|PubMed:26428751, ECO:0000269|PubMed:28892125}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.818
RVIS EVS: -0.03
RVIS percentile EVS: 51.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.690

Gene Damage Prediction

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