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…

DNmechanismLOEUF 0.79

Clinical Summary— BTBD1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

45 VUS of 60 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.6357th %ile

GOF

0.6247th %ile

LOF

0.3746th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

60 submitted variants in ClinVar

ClinVar

Classification Summary

VUS45

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	44	45
Likely Benign	0	1	1
Benign	0	0	0
Total	1	45	46

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap BTBD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →