TRIP12

Chr 2AD

thyroid hormone receptor interactor 12

Also known as: MRD49, TRIP-12, TRIPC, ULF

NCBI Gene: 9320 ENSG00000153827 UniProt: Q14669 OMIM: 604506

The encoded E3 ubiquitin-protein ligase degrades the p19ARF tumor suppressor isoform and regulates USP7 stability in DNA damage response pathways. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder. The gene is extremely intolerant to loss-of-function variants, indicating haploinsufficiency as the disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is an E3 ubiquitin-protein ligase involved in the degradation of the p19ARF/ARF isoform of CDKN2A, a tumor suppressor. The encoded protein also plays a role in the DNA damage response by regulating the stability of USP7, which regulates tumor suppressor p53. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— TRIP12

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

74 unique Pathogenic / Likely Pathogenic· 301 VUS of 517 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 9.34

OE 0.02 (0.01–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.64Z-score

OE missense 0.60 (0.56–0.64)

639 obs / 1065.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.06)

0≤0.351.4

Missense OE?0.60 (0.56–0.64)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 2 / 105.5Missense obs/exp: 639 / 1065.2Syn Z: -0.76

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTRIP12-related intellectual disability with or without autism spectrum disorderLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.2597th %ile

LOF

0.84top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 85% of P/LP variants are LoF · LOEUF 0.06 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28251352 ↗

ClinVar Variant Classifications

517 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50

Likely Pathogenic24

VUS301

Likely Benign40

Benign33

Conflicting10

Pathogenic

Likely Pathogenic

301

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	48	1	1	0	50
Likely Pathogenic	15	6	3	0	24
VUS	6	279	15	1	301
Likely Benign	0	22	1	17	40
Benign	0	0	29	4	33
Conflicting	—				10
Total	69	308	49	22	458

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap TRIP12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →