USP19

Chr 3

ubiquitin specific peptidase 19

Also known as: ZMYND9

NCBI Gene: 10869 ENSG00000172046 UniProt: O94966 OMIM: 614471

USP19 encodes a deubiquitinating enzyme that removes ubiquitin from proteins to prevent their degradation, regulating processes including muscle development, endoplasmic reticulum protein quality control, and cellular responses to hypoxia. Mutations cause autosomal recessive developmental and epileptic encephalopathy with early-onset seizures and severe developmental delay. The gene is highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. This dynamic process, involving ubiquitin conjugating enzymes and deubiquitinating enzymes, adds and removes ubiquitin. Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. This protein is a ubiquitin protein ligase and plays a role in muscle wasting. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 6.66

OE 0.11 (0.06–0.20)

Highly constrained

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

Missense Constraint?

1.99Z-score

OE missense 0.81 (0.76–0.86)

691 obs / 854.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.20)

0≤0.351.4

Missense OE?0.81 (0.76–0.86)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 7 / 64.9Missense obs/exp: 691 / 854.7Syn Z: 1.63

Background carrier burden — how many people carry a rare variant somewhere in USP19?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,728 rare PASS variants

Rare truncating (LoF)

1 in 1,500

115 rare PASS variants

Rare synonymous (reference)

1 in 58

779 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for USP19. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 44	1 in 2,000
South Asian	~43k	1 in 26	1 in 1,000
Remaining (unassigned)	~30k	1 in 30	1 in 2,800
European (Finnish)	~27k	1 in 80	1 in 1,200
Admixed American	~22k	1 in 28	1 in 670
African / African American	~21k	1 in 40	1 in 1,200
East Asian	~20k	1 in 45	1 in 2,200
Ashkenazi Jewish	~13k	1 in 110	1 in 1,400
Middle Eastern	~2,884	1 in 51	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 26 coding exons well covered in gnomAD exomes; exons 3, 27 marginal. Genomes: all 26.? see exons ↓