TRIOBP

Chr 22AR

TRIO and F-actin binding protein

Also known as: DFNB28, HRIHFB2122, TAP68, TARA, dJ37E16.4

NCBI Gene: 11078 ENSG00000100106 UniProt: Q9H2D6 OMIM: 609761

The protein regulates actin cytoskeletal organization by directly binding and stabilizing filamentous F-actin and preventing its depolymerization, and is essential for correct mitotic progression. Mutations cause autosomal recessive nonsyndromic deafness (DFNB28). The gene shows high tolerance to loss-of-function variants (very low pLI), consistent with its autosomal recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Nov 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.711 OMIM phenotype

Clinical Summary— TRIOBP

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Gene-Disease Validity (ClinGen)

hearing loss, autosomal recessive · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

68 unique Pathogenic / Likely Pathogenic· 318 VUS of 852 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TRIOBP

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 4.07

OE 0.58 (0.47–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.20Z-score

OE missense 1.01 (0.97–1.06)

1396 obs / 1375.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.58 (0.47–0.71)

0≤0.351.4

Missense OE?1.01 (0.97–1.06)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 63 / 108.8Missense obs/exp: 1396 / 1375.5Syn Z: 1.20

This gene — mechanism propensity

0.6841th %ile

GOF

0.4973th %ile

LOF

0.4233th %ile

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

DNprediction above median

LOF99% of P/LP variants are LoF

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

852 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic33

VUS318

Likely Benign299

Benign92

Conflicting47

Pathogenic

Likely Pathogenic

318

VUS

299

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	0	0	0	35
Likely Pathogenic	32	1	0	0	33
VUS	5	286	17	10	318
Likely Benign	1	50	108	140	299
Benign	0	27	54	11	92
Conflicting	—				47
Total	73	364	179	161	824

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap TRIOBP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →