OTUD7A

Chr 15AR

OTU deubiquitinase 7A

Also known as: C15orf16, C16ORF15, CEZANNE2, NEDHS, OTUD7

NCBI Gene: 161725 ENSG00000169918 UniProt: Q8TE49 OMIM: 612024

OTUD7A encodes a deubiquitinase that cleaves lysine-11-linked polyubiquitin chains and regulates nuclear factor kappa B signaling through its action on TRAF6. Mutations cause autosomal recessive neurodevelopmental disorder with hypotonia and seizures. The gene is highly constrained against loss-of-function mutations (pLI 0.95, LOEUF 0.33), indicating that functional copies are essential for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a deubiquitinizing enzyme and possible tumor suppressor. The encoded protein acts on TNF receptor associated factor 6 (TRAF6) to control nuclear factor kappa B expression. However, this gene is downregulated by SNAIL1 in hepatocellular carcinoma cells, contributing to their progression and malignancy. [provided by RefSeq, Aug 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.331 OMIM phenotype

Clinical Summary— OTUD7A

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 156 VUS of 184 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — OTUD7A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.952

Z-score 4.39

OE 0.16 (0.08–0.33)

Highly constrained

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

Missense Constraint?

2.86Z-score

OE missense 0.62 (0.56–0.69)

284 obs / 456.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.16 (0.08–0.33)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 5 / 31.6Missense obs/exp: 284 / 456.2Syn Z: -0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedOTUD7A-related 15q13.3 deletions phenocopyLOFAD

This gene — mechanism propensity

0.3495th %ile

GOF

0.4973th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.33

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

184 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS156

Likely Benign12

Benign10

Pathogenic

Likely Pathogenic

156

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	1	0	0	0	1
VUS	5	150	1	0	156
Likely Benign	0	1	2	9	12
Benign	0	3	1	6	10
Total	7	155	4	15	181

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

View in ClinVar →

189 pathogenic / likely-pathogenic (of 279) ClinVar copy-number / structural variants overlap OTUD7A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →