SCUBE3

protein-coding

signal peptide, CUB domain and EGF like domain containing 3

Gene summary

This gene encodes a member of the signal peptide, complement subcomponents C1r/C1s, Uegf, bone morphogenetic protein-1 and epidermal growth factor-like domain containing protein family. Overexpression of this gene in human embryonic kidney cells results in secretion of a glycosylated form of the protein that forms oligomers and tethers to the cell surface. This gene is upregulated in lung cancer tumor tissue compared to healthy tissue and is associated with loss of the epithelial marker E-cadherin and with increased expression of vimentin, a mesenchymal marker. In addition, the protein encoded by this gene is a transforming growth factor beta receptor ligand, and when secreted by cancer cells, it can be cleaved in vitro to release the N-terminal epidermal growth factor-like repeat domain and the C-terminal complement subcomponents C1r/C1s domain. Both the full length protein and C-terminal fragment can bind to the transforming growth factor beta type II receptor to promote the epithelial-mesenchymal transition and tumor angiogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Previous symbols:

CEGF3

MANE transcript

NM_152753.4

Inheritance

ClinVar variants

P:13U:143B:10

Top phenotype

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr6:35,213,956-35,253,079

External References & Databases

Ensembl (ENSG00000146197)

Transcript & Mutation Effects

hg38 • Region Span ~39.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030953

Submitter: G2P

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030953

Submitter: Labcorp Genetics (formerly Invitae)

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030953

Submitter: Ambry Genetics

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030953

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomaliesAR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dental; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Among other features, the condition can involve arrhythmias, and awareness can allow early diagnosis and management

Refs: 33308444

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCUBE3 variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 121

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2Total: 25

not providedTotal: 19

Short statureTotal: 8

Abnormal facial shapeTotal: 8

Abnormality of the dentitionTotal: 8

Abnormality of the skeletal systemTotal: 8

not specifiedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152753.4. 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			1 clinvar	4 clinvar	1 clinvar	6
missense	2 clinvar	1 clinvar	140 clinvar	3 clinvar	2 clinvar	148
nonsense	3 clinvar	3 clinvar				6
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	1 clinvar			5
Total	8	5	143	7	3	166

Highest pathogenic variant AF is 0.000025993711

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152753.4	RefSeq	NP_689966.2	22	MANE Select
ENST00000274938.8	Ensembl	ENSP00000274938.7	22	MANE Select
NM_001303136.2	RefSeq	NP_001290065.1	22	Standard
ENST00000889524.1	Ensembl	ENSP00000559583.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Extracellular matrix organization
Degradation of the extracellular matrix

Biological Process

extracellular matrix disassembly
positive regulation of smoothened signaling pathway
protein homooligomerization
protein heterooligomerization

Molecular Function

calcium ion binding
protein binding

Cellular Component

extracellular space
plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274938
Coding exons: 22
Length: 38667
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.70	425	613	0.693	0.0000371	6552
Missense (PolyPhen)		147	249.98	0.58804		2711
Synonymous	2.27	191	235	0.812	0.0000145	1895
Loss of Function	5.80	7	52.2	0.134	0.00000289	593

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to TGFBR2 and activates TGFB signaling. In lung cancer cells, could serve as an endogenous autocrine and paracrine ligand of TGFBR2, which could regulate TGFBR2 signaling and hence modulate epithelial-mesenchymal transition and cancer progression. {ECO:0000269|PubMed:21441952}.;

Recessive Scores

pRec: 0.0910

Intolerance Scores

LoFtool: 0.0393
RVIS EVS: -0.22
RVIS percentile EVS: 37.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.357

Gene Damage Prediction

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