KIAA0753

Chr 17

KIAA0753

Also known as: JBTS38, MNR, OFIP, SRTD21

NCBI Gene: 9851 ENSG00000198920 UniProt: Q2KHM9

The protein regulates centriole duplication and promotes centrosomal localization of key cell cycle proteins, and may function in cilium assembly. Mutations cause autosomal recessive ciliopathies including Joubert syndrome 38, orofaciodigital syndrome XV, and short-rib thoracic dysplasia 21 without polydactyly. The gene shows minimal constraint against loss-of-function variants (LOEUF 1.105), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.10

Clinical Summary— KIAA0753

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

48 unique Pathogenic / Likely Pathogenic· 250 VUS of 574 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 0.91

OE 0.87 (0.69–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.21Z-score

OE missense 0.97 (0.91–1.05)

517 obs / 530.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.87 (0.69–1.10)

0≤0.351.4

Missense OE?0.97 (0.91–1.05)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 47 / 54.3Missense obs/exp: 517 / 530.4Syn Z: 0.67

This gene — mechanism propensity

0.6162th %ile

GOF

0.6053th %ile

LOF

0.4331th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF94% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

574 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25

Likely Pathogenic23

VUS250

Likely Benign184

Benign59

Conflicting14

Pathogenic

Likely Pathogenic

250

VUS

184

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	2	0	0	25
Likely Pathogenic	22	1	0	0	23
VUS	2	239	7	2	250
Likely Benign	1	12	72	99	184
Benign	0	12	38	9	59
Conflicting	—				14
Total	48	266	117	110	555

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap KIAA0753 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →