USP7

Chr 16AD

ubiquitin specific peptidase 7

Also known as: C16DELp13.2, DEL16P13.2, HAFOUS, HAUSP, TEF1

NCBI Gene: 7874 ENSG00000187555 OMIM: 602519

USP7 encodes a deubiquitinating enzyme that removes ubiquitin from target proteins including p53, PTEN, and components involved in DNA repair and chromatin regulation. Mutations cause Hao-Fountain syndrome, a neurodevelopmental disorder with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the peptidase C19 family, which includes ubiquitinyl hydrolases. This protein deubiquitinates target proteins such as p53 (a tumor suppressor protein) and WASH (essential for endosomal protein recycling), and regulates their activities by counteracting the opposing ubiquitin ligase activity of proteins such as HDM2 and TRIM27, involved in the respective process. Mutations in this gene have been implicated in a neurodevelopmental disorder. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— USP7

🧬

Gene-Disease Validity (ClinGen)

Hao-Fountain syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

56 unique Pathogenic / Likely Pathogenic· 243 VUS of 609 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — USP7

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 8.04

OE 0.01 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.65Z-score

OE missense 0.36 (0.32–0.41)

225 obs / 621.1 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.01 (0.00–0.06)

0≤0.351.4

Missense OE?0.36 (0.32–0.41)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 1 / 77.2Missense obs/exp: 225 / 621.1Syn Z: -2.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongUSP7-related developmental disorderLOFAD

This gene — mechanism propensity

0.2997th %ile

GOF

0.3293th %ile

LOF

0.73top 10%

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

LOFprediction above median · 1 literature citation · 70% of P/LP variants are LoF · LOEUF 0.06 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFThe consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.1

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

References

1.PMID 30679821 ↗

ClinVar Variant Classifications

609 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic35

VUS243

Likely Benign222

Benign50

Conflicting5

Pathogenic

Likely Pathogenic

243

VUS

222

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	1	1	0	21
Likely Pathogenic	20	14	1	0	35
VUS	1	213	24	5	243
Likely Benign	0	13	122	87	222
Benign	0	4	37	9	50
Conflicting	—				5
Total	40	245	185	101	576

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 79) ClinVar copy-number / structural variants overlap USP7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →