TBC1D10B

Chr 16

TBC1 domain family member 10B

Also known as: EPI64B, FP2461

NCBI Gene: 26000 ENSG00000169221 UniProt: Q4KMP7 OMIM: 613620

TBC1D10B encodes a GTPase-activating protein that regulates RAB3A, RAB22A, RAB27A, and RAB35, which are essential for intracellular vesicle trafficking. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.21), indicating that mutations likely cause severe developmental phenotypes. However, no specific disease associations or inheritance patterns have been established for this gene.

OMIM ResearchSummary from RefSeq, UniProt

Small G proteins of the RAB family (see MIM 179508) function in intracellular vesicle trafficking by switching from the GTP-bound state to the GDP-bound state with the assistance of guanine nucleotide exchange factors (GEFs; see MIM 609700) and GTPase-activating proteins (GAPs). TBC1D10B functions as a GAP for several proteins of the Rab family (Ishibashi et al., 2009 [PubMed 19077034]).[supplied by OMIM, Nov 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.21

Clinical Summary— TBC1D10B

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

136 VUS of 148 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.999

Z-score 4.69

OE 0.07 (0.03–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.95Z-score

OE missense 0.73 (0.66–0.80)

288 obs / 397.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.21)

0≤0.351.4

Missense OE?0.73 (0.66–0.80)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 2 / 29.5Missense obs/exp: 288 / 397.1Syn Z: 0.86

This gene — mechanism propensity

0.3892th %ile

GOF

0.6639th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.21

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

148 submitted variants in ClinVar

ClinVar

Classification Summary

VUS136

Likely Benign2

136

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	136	136
Likely Benign	2	2
Benign	0	0
Total	138	138

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap TBC1D10B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →