KBTBD7

Chr 13

kelch repeat and BTB domain containing 7

NCBI Gene: 84078 ENSG00000120696 UniProt: Q8WVZ9

KBTBD7 encodes a substrate adapter protein that functions in E3 ubiquitin ligase complexes to regulate TIAM1 degradation, thereby controlling RAC1 signaling pathways involved in cytoskeletal organization, cell migration, and cell proliferation. Pathogenic variants cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, presenting in early infancy with seizures and severe developmental delays. This gene affects critical neurodevelopmental processes through dysregulation of cellular signaling pathways essential for brain development.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a transcriptional activator, having been shown to increase the transcription of activator protein-1 and serum response element. The encoded protein can also form a complex with KBTBD6 and CUL3, which regulates the ubiquitylation and degradation of TIAM1, which is a regulator of RAC1. [provided by RefSeq, Jul 2016]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.92

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 1.83

OE 0.57 (0.36–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.66Z-score

OE missense 0.76 (0.69–0.84)

296 obs / 388.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.36–0.92)

0≤0.351.4

Missense OE?0.76 (0.69–0.84)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 12 / 21.1Missense obs/exp: 296 / 388.1Syn Z: 0.24

Background carrier burden — how many people carry a rare variant somewhere in KBTBD7?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

708 rare PASS variants

Rare truncating (LoF)

1 in 3,100

62 rare PASS variants

Rare synonymous (reference)

1 in 130

326 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KBTBD7. 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 190	1 in 3,000
South Asian	~43k	1 in 83	1 in 6,200
Remaining (unassigned)	~30k	1 in 180	1 in 5,000
European (Finnish)	~27k	1 in 300	1 in 4,400
Admixed American	~22k	1 in 120	1 in 1,400
African / African American	~21k	1 in 96	1 in 3,600
East Asian	~20k	1 in 77	≈ 1 in 4,000
Ashkenazi Jewish	~13k	1 in 570	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 120	none seen

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓