BTBD19

Chr 1

BTB domain containing 19

NCBI Gene: 149478 ENSG00000222009 UniProt: C9JJ37

The protein functions as a substrate adaptor for cullin-3-based E3 ubiquitin ligases, targeting specific proteins for ubiquitination and degradation. Mutations cause autosomal recessive intellectual disability with seizures and dysmorphic features. The gene shows moderate constraint against loss-of-function variants, suggesting some functional importance but tolerance to haploinsufficiency.

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.67

Clinical Summary— BTBD19

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

48 VUS of 56 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.67LOEUF

pLI 0.051

Z-score 2.51

OE 0.32 (0.17–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.78Z-score

OE missense 0.62 (0.53–0.73)

111 obs / 177.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.17–0.67)

0≤0.351.4

Missense OE?0.62 (0.53–0.73)

0≤0.61.4

Synonymous OE?0.65

0≤1.21.6

LoF obs/exp: 5 / 15.8Missense obs/exp: 111 / 177.8Syn Z: 2.49

This gene — mechanism propensity

0.6937th %ile

GOF

0.7125th %ile

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

56 submitted variants in ClinVar

ClinVar

Classification Summary

VUS48

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	48	48
Likely Benign	3	3
Benign	0	0
Total	51	51

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap BTBD19 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →