TRIM16

Chr 17

tripartite motif containing 16

Also known as: EBBP

NCBI Gene: 10626 ENSG00000221926 UniProt: O95361 OMIM: 609505

The TRIM16 protein functions as an E3 ubiquitin ligase that regulates autophagy and protects cells against oxidative stress by modulating protein aggregate degradation and the NRF2 signaling pathway. Mutations cause autosomal recessive intellectual disability with seizures and variable additional features including microcephaly and developmental delays. This gene shows very low constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a tripartite motif (TRIM) family member that contains two B box domains and a coiled-coiled region that are characteristic of the B box zinc finger protein family. While it lacks a RING domain found in other TRIM proteins, the encoded protein can homodimerize or heterodimerize with other TRIM proteins and has E3 ubiquitin ligase activity. This gene is also a tumor suppressor and is involved in secretory autophagy. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.13

Clinical Summary— TRIM16

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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

86 VUS of 104 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?

1.13LOEUF

pLI 0.000

Z-score 1.10

OE 0.74 (0.50–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.34Z-score

OE missense 0.95 (0.86–1.04)

300 obs / 316.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.50–1.13)

0≤0.351.4

Missense OE?0.95 (0.86–1.04)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 16 / 21.5Missense obs/exp: 300 / 316.8Syn Z: 1.10

This gene — mechanism propensity

0.75top 25%

GOF

0.76top 25%

LOF

0.2484th %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

104 submitted variants in ClinVar

ClinVar

Classification Summary

VUS86

Likely Benign9

Benign1

VUS

Likely Benign

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	86	0	86
Likely Benign	7	2	9
Benign	1	0	1
Total	94	2	96

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap TRIM16 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →