CUL7

protein-coding

cullin 7, the group of Cullins

Gene summary

The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex. The encoded protein interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

Previous symbols:

KIAA0076

MANE transcript

NM_014780.5

Inheritance

ClinVar variants

P:134U:461B:292

Top phenotype

Three M syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr6:43,037,617-43,053,943

External References & Databases

Ensembl (ENSG00000044090)

Transcript & Mutation Effects

hg38 • Region Span ~16.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3M syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010117

Submitter: G2P

3M syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010117

Submitter: Ambry Genetics

3-M syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007477

Submitter: Orphanet

3M syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010117

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Three M syndrome 1AR

Manifestation: Craniofacial; 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: 16142236; 17675530; 19225462; 21166787; 22624670; 22974575

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CUL7 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 738

Inborn genetic diseasesTotal: 229

3M syndrome 1Total: 211

not specifiedTotal: 145

CUL7-related disorderTotal: 59

3-M syndromeTotal: 14

Monogenic short statueTotal: 3

Short statureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014780.5. 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			21 clinvar	238 clinvar	7 clinvar	266
missense		7 clinvar	427 clinvar	45 clinvar	2 clinvar	481
nonsense	30 clinvar	15 clinvar	2 clinvar			47
start loss						0
frameshift	36 clinvar	22 clinvar	3 clinvar			61
splice donor/acceptor (+/-2bp)	7 clinvar	17 clinvar	8 clinvar			32
Total	73	61	461	283	9	887

Highest pathogenic variant AF is 0.00016926517

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014780.5	RefSeq	NP_055595.2	25	MANE Select
ENST00000265348.9	Ensembl	ENSP00000265348.4	25	MANE Select
NM_001168370.2	RefSeq	NP_001161842.2	25	Standard
NM_001374872.1	RefSeq	NP_001361801.1	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
XBP1(S) activates chaperone genes
Post-translational protein modification
Metabolism of proteins
Immune System

Biological Process

microtubule cytoskeleton organization
mitotic cytokinesis
vasculogenesis
epithelial to mesenchymal transition
placenta development

Molecular Function

protein binding
ubiquitin protein ligase binding

Cellular Component

anaphase-promoting complex
cytoplasm
Golgi apparatus
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000535468
Coding exons: 26
Length: 16329
Individuals with no LoFs: 125647
Homozygous LoFs: 0
Heterozygous LoFs: 101
Defined: 125748
p: 0.000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.543	959	1.01e+3	0.952	0.0000653	11513
Missense (PolyPhen)		310	339.81	0.91228		3945
Synonymous	-0.212	430	424	1.01	0.0000266	3706
Loss of Function	3.59	47	82.0	0.573	0.00000460	878

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00099	0.00098	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00065	0.00065	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00073	0.00072	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediates the ubiquitination of target proteins. Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695). Interaction with CUL9 is required to inhibit CUL9 activity and ubiquitination of BIRC5 (PubMed:24793696). Core component of a Cul7-RING ubiquitin-protein ligase with FBXW8, which mediates ubiquitination and consequent degradation of target proteins such as GORASP1, IRS1 and MAP4K1/HPK1 (PubMed:21572988, PubMed:24362026). Ubiquitination of GORASP1 regulates Golgi morphogenesis and dendrite patterning in brain (PubMed:21572988). Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2) (PubMed:18498745). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation (PubMed:24362026). Acts as a regulator in trophoblast cell epithelial-mesenchymal transition and placental development (PubMed:20139075). Does not promote polyubiquitination and proteasomal degradation of p53/TP53 (PubMed:16547496, PubMed:17332328). While the Cul7-RING(FBXW8) and the 3M complexes are associated and involved in common processes, CUL7 and the Cul7-RING(FBXW8) complex may be have additional functions. {ECO:0000269|PubMed:16547496, ECO:0000269|PubMed:17332328, ECO:0000269|PubMed:18498745, ECO:0000269|PubMed:20139075, ECO:0000269|PubMed:21572988, ECO:0000269|PubMed:24362026, ECO:0000269|PubMed:24793695, ECO:0000269|PubMed:24793696}.;
Disease: DISEASE: 3M syndrome 1 (3M1) [MIM:273750]: An autosomal recessive disorder characterized by severe pre- and postnatal growth retardation, facial dysmorphism, large head circumference, and normal intelligence and endocrine function. Skeletal changes include long slender tubular bones and tall vertebral bodies. {ECO:0000269|PubMed:16142236, ECO:0000269|PubMed:17675530, ECO:0000269|PubMed:23018678}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.123

Intolerance Scores

LoFtool: 0.253
RVIS EVS: -1.53
RVIS percentile EVS: 3.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.754

Gene Damage Prediction

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