TBC1D3F

Chr 17

TBC1 domain family member 3F

NCBI Gene: 84218 ENSG00000275954 UniProt: A6NER0 OMIM: 610809

The protein acts as a GTPase activating protein specifically for RAB5, which regulates endocytic trafficking at the plasma membrane. This gene shows very low constraint against loss-of-function variants (pLI = 0.00001, LOEUF = 1.95), and no definitive disease associations have been established in the provided data.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable GTPase activator activity. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.95

Clinical Summary— TBC1D3F

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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

2 VUS of 6 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.95LOEUF

pLI 0.000

Z-score -1.22

OE 1.70 (0.82–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.06Z-score

OE missense 1.03 (0.79–1.35)

37 obs / 36.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.70 (0.82–1.95)

0≤0.351.4

Missense OE?1.03 (0.79–1.35)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 6 / 3.5Missense obs/exp: 37 / 36.0Syn Z: 0.38

This gene — mechanism propensity

0.7327th %ile

GOF

0.78top 25%

LOF

0.2678th %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

6 submitted variants in ClinVar

ClinVar

Classification Summary

VUS2

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	2	0	2
Likely Benign	3	1	4
Benign	0	0	0
Total	5	1	6

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 56) ClinVar copy-number / structural variants overlap TBC1D3F — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →