OFD1

Chr XXLDXLR

OFD1 centriole and centriolar satellite protein

Also known as: 71-7A, CXorf5, JBTS10, RP23, SGBS2

NCBI Gene: 8481 ENSG00000046651 UniProt: O75665

This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

Orofaciodigital syndrome IMIM #311200

XLD

?Retinitis pigmentosa 23MIM #300424

XLR

Joubert syndrome 10MIM #300804

XLR

Orofaciodigital syndrome IMIM #311200

XLD

Simpson-Golabi-Behmel syndrome, type 2MIM #300209

XLR

326

ClinVar variants

Pathogenic / LP

0.96

pLI score· haploinsufficient

Active trials

Clinical Summary— OFD1

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Gene-Disease Validity (ClinGen)

OFD1-related ciliopathy · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

76 Pathogenic / Likely Pathogenic· 148 VUS of 326 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.32LOEUF

pLI 0.960

Z-score 4.91

OE 0.17 (0.10–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.32Z-score

OE missense 0.95 (0.87–1.04)

350 obs / 367.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.10–0.32)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.87–1.04)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06

0≤1.21.6

LoF obs/exp: 7 / 40.9Missense obs/exp: 350 / 367.2Syn Z: -0.51

ClinVar Variant Classifications

326 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic20

VUS148

Likely Benign86

Benign5

Conflicting11

Pathogenic

Likely Pathogenic

148

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	3	31	0	56
Likely Pathogenic	13	0	7	0	20
VUS	0	124	18	6	148
Likely Benign	0	6	44	36	86
Benign	0	2	2	1	5
Conflicting	—				11
Total	35	135	102	43	326

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

View in ClinVar →

Protein Context — Lollipop Plot

OFD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

OFD1-related Simpson-Golabi-Behmel syndrome

limited

Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product

Skin

G2P ↗

OFD1-related Joubert syndrome

definitive

Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product

Dev. DisordersEye

G2P ↗

OFD1-related oral-facial-digital syndrome

definitive

Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product

Dev. DisordersSkeletal

G2P ↗

OFD1-related retinitis pigmentosa

strong

Monoallelic X HemizygousUndeterminedUncertain

Eye

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

OROFACIODIGITAL SYNDROME I; OFD1

MIM #311200 · #

Orofaciodigital syndrome I

MIM #311200