UBASH3A

Chr 21

ubiquitin associated and SH3 domain containing A

Also known as: CLIP4, STS-2, TULA, TULA-1

NCBI Gene: 53347 ENSG00000160185 UniProt: P57075 OMIM: 605736

This gene encodes a negative regulator of T-cell signaling that interferes with receptor degradation and promotes accumulation of activated receptors including T-cell receptors and growth factor receptors on the cell surface. Mutations cause autosomal recessive primary immunodeficiency with recurrent infections, lymphoproliferation, and autoimmune manifestations typically presenting in early childhood. The gene shows minimal constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes one of two family members belonging to the T-cell ubiquitin ligand (TULA) family. Both family members can negatively regulate T-cell signaling. This family member can facilitate growth factor withdrawal-induced apoptosis in T cells, which may occur via its interaction with AIF, an apoptosis-inducing factor. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.92

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.93

OE 0.64 (0.45–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.34Z-score

OE missense 0.95 (0.87–1.04)

375 obs / 394.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.45–0.92)

0≤0.351.4

Missense OE?0.95 (0.87–1.04)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 21 / 33.0Missense obs/exp: 375 / 394.2Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in UBASH3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

934 rare PASS variants

Rare truncating (LoF)

1 in 880

131 rare PASS variants

Rare synonymous (reference)

1 in 68

375 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UBASH3A. 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 54	1 in 860
South Asian	~43k	1 in 42	1 in 940
Remaining (unassigned)	~30k	1 in 43	1 in 1,100
European (Finnish)	~27k	1 in 120	1 in 2,200
Admixed American	~22k	1 in 38	1 in 1,100
African / African American	~21k	1 in 43	1 in 990
East Asian	~20k	1 in 52	1 in 850
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 45	≈ 1 in 830

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): 14 of 15 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 15.? see exons ↓