KIAA0753

protein-coding

KIAA0753

Gene summary

This gene encodes a subunit of a protein complex that regulates ciliogenesis and cilia maintenance. The encoded protein has also been shown to regulate centriolar duplication. Mutations in this gene cause an orofaciodigital syndrome and a form of Joubert syndrome in human patients. [provided by RefSeq, May 2017]

MANE transcript

NM_014804.3

Inheritance

ClinVar variants

P:63U:257B:149

Top phenotype

Joubert syndrome 38; Short-rib thoracic dysplasia 21 without polydactyly

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr17:6,578,147-6,640,711

External References & Databases

Ensembl (ENSG00000198920)

Transcript & Mutation Effects

hg38 • Region Span ~62.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

orofaciodigital syndrome XVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014932

Submitter: Ambry Genetics

short-rib thoracic dysplasia 21 without polydactylySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030356

Submitter: PanelApp Australia

orofaciodigital syndrome type 6SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010176

Submitter: Orphanet

orofaciodigital syndrome XVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014932

Submitter: Labcorp Genetics (formerly Invitae)

Jeune syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018770

Submitter: Orphanet

Jeune syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018770

Submitter: Franklin by Genoox

A patient with Jeune syndrome characterized by a short-rib skeletal dysplasia underwent DNA examiantion which revealed Homozygosity for the c.943C > T sequence alteration in KIAA0753 gene. In addition previous reports of two brothers with Joubert syndrome

Clinical Genomic Database (CGD)

Joubert syndrome 38; Short-rib thoracic dysplasia 21 without polydactylyAR

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: An affected individual with Joubert syndrome has been described with manifestations including hypopituitarism, and some manifestations (eg, hypothyroidism) may benefit from medical management; Individuals with Short-rib thoracic dysplasia 21 without polydactyly have been described as having respiratory sequelae, including frequent infections, and awareness may allow aggressive pulmonary management

Refs: 26643951; 28220259; 29138412; 31816441; 33875766; 34016807

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIAA0753 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 426

Inborn genetic diseasesTotal: 165

not specifiedTotal: 99

KIAA0753-related disorderTotal: 47

Short-rib thoracic dysplasia 21 without polydactylyTotal: 14

Joubert syndrome 38Total: 12

Orofaciodigital syndrome XVTotal: 12

Jeune thoracic dystrophyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014804.3. 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	1 clinvar		4 clinvar	110 clinvar	1 clinvar	116
missense	1 clinvar	1 clinvar	245 clinvar	33 clinvar	4 clinvar	284
nonsense	6 clinvar	19 clinvar		1 clinvar		26
start loss	1 clinvar					1
frameshift	8 clinvar	12 clinvar	2 clinvar			22
splice donor/acceptor (+/-2bp)	2 clinvar	12 clinvar	6 clinvar			20
Total	19	44	257	144	5	469

Highest pathogenic variant AF is 0.00020291428

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014804.3	RefSeq	NP_055619.2	18	MANE Select
ENST00000361413.8	Ensembl	ENSP00000355250.3	18	MANE Select
NM_001351225.2	RefSeq	NP_001338154.1	14	Standard
ENST00000542826.6	Ensembl	ENSP00000444946.3	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
si:dkey-243i1.1	Danio rerio	Structure: cranial cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

si:dkey-243i1.1

Danio rerio

Structure: cranial cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

centriole replication
protein localization to centrosome

Molecular Function

protein binding

Cellular Component

centrosome
centriole
cytosol
centriolar satellite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361413
Coding exons: 18
Length: 62780
Individuals with no LoFs: 124521
Homozygous LoFs: 1
Heterozygous LoFs: 278
Defined: 124800
p: 0.00112

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.207	517	530	0.975	0.0000284	6338
Missense (PolyPhen)		141	152.66	0.92361		1884
Synonymous	0.673	181	193	0.938	0.0000107	1847
Loss of Function	0.913	47	54.3	0.866	0.00000318	601

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0093	0.0093	notable
Latino/Admixed American	0.00077	0.00075	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00056	0.00056	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00060	0.00060	rare
South Asian	0.00062	0.00062	rare
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in centriole duplication. Positively regulates CEP63 centrosomal localization. Required for WDR62 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:24613305, PubMed:26297806). {ECO:0000269|PubMed:26297806}.;
Disease: DISEASE: Orofaciodigital syndrome 15 (OFD15) [MIM:617127]: A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD15 features include facial dysmorphism, lobulated tongue, clefting of the alveolar ridges, left hand postaxial polydactyly, broad right hallux and left hallux duplication, and intermittent respiratory difficulty. Brain anomalies include vermis hypoplasia with molar tooth sign, agenesis of corpus callosum, and ventricular dilation. OFD15 inheritance is autosomal recessive. {ECO:0000269|PubMed:26643951}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.583
RVIS EVS: 2.14
RVIS percentile EVS: 97.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0491

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High