BTBD1

Chr 15

BTB domain containing 1

Also known as: C15orf1, NS5ATP8

NCBI Gene: 53339 ENSG00000064726 UniProt: Q9H0C5 OMIM: 608530

The protein encoded by BTBD1 functions as a substrate-specific adapter for E3 ubiquitin ligase complexes that target proteins for degradation, and contains a BTB/POZ domain for protein-protein interactions along with a C-terminus that binds topoisomerase I. Mutations in BTBD1 cause autosomal recessive intellectual disability with seizures and dysmorphic features, typically presenting in early childhood. This gene is extremely intolerant to loss-of-function variants, indicating that proper protein dosage is critical for normal neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

The C-terminus of the protein encoded by this gene binds topoisomerase I. The N-terminus contains a proline-rich region and a BTB/POZ domain (broad-complex, Tramtrack and bric a brac/Pox virus and Zinc finger), both of which are typically involved in protein-protein interactions. Subcellularly, the protein localizes to cytoplasmic bodies. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.79

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.000

Z-score 2.30

OE 0.46 (0.29–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.42Z-score

OE missense 0.75 (0.66–0.84)

185 obs / 247.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.29–0.79)

0≤0.351.4

Missense OE?0.75 (0.66–0.84)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 10 / 21.5Missense obs/exp: 185 / 247.8Syn Z: 0.76

Background carrier burden — how many people carry a rare variant somewhere in BTBD1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

584 rare PASS variants

Rare truncating (LoF)

1 in 2,000

107 rare PASS variants

Rare synonymous (reference)

1 in 220

264 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BTBD1. 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 170	1 in 1,900
South Asian	~43k	1 in 110	1 in 580
Remaining (unassigned)	~30k	1 in 110	1 in 730
European (Finnish)	~27k	1 in 310	≈ 1 in 26,000
Admixed American	~22k	1 in 150	1 in 3,200
African / African American	~21k	1 in 120	1 in 1,600
East Asian	~20k	1 in 120	1 in 2,800
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 92	≈ 1 in 2,900

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): 6 of 8 coding exons well covered in gnomAD exomes; exons 1, 6 marginal. Genomes: all 8.? see exons ↓