TRIP12

protein-coding

thyroid hormone receptor interactor 12, the group of HECT domain containing|Armadillo like helical domain containing

Gene summary

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]

MANE transcript

NM_001348323.3

Inheritance

ClinVar variants

P:114U:460B:126

Top phenotype

Clark-Baraitser syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr2:229,763,837-229,923,239

External References & Databases

Ensembl (ENSG00000153827)

Transcript & Mutation Effects

hg38 • Region Span ~159.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*TRIP12* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2008 (Doco-Fenzy et al., PMID: 18822396). Individuals with variants in this gene have been reported to have delayed psychomotor development with delayed walking, mildly impaired intellectual development, learning difficulties, autistic features, or behavioral abnormalities. Most had fluent speech, although several patients had delayed speech. Additional features included hypotonia (4 patients), seizures (3 patients), and strabismus (2 patients). Given the spectrum of neurodevelopmental features observed, this gene was curated for the disease entity "complex neurodevelopmental disorder". Twenty-seven variants (missense, in-frame indel, nonsense, frameshift, large deletions, etc.) have been reported in 25 probands in 6 publications (PMIDs: 25418537, 27848077, 18822396, 27479843, 28251352, 32424948) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The presumed mechanism of pathogenicity based on published evidence is loss of function. In summary, *TRIP12* is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Expert Panel on April 5th, 2022 (SOP Version 9).

Clark-Baraitser syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030914

Submitter: G2P

Clark-Baraitser syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030914

Submitter: PanelApp Australia

Clark-Baraitser syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030914

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Clark-Baraitser syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25363768; 27479843; 27848077; 28251352

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRIP12 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 359

Inborn genetic diseasesTotal: 172

Clark-Baraitser syndromeTotal: 140

not specifiedTotal: 80

TRIP12-related disorderTotal: 64

Intellectual disabilityTotal: 8

See casesTotal: 7

Neurodevelopmental disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001348323.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	73 clinvar	2 clinvar	82
missense	1 clinvar	12 clinvar	431 clinvar	51 clinvar		495
nonsense	22 clinvar	10 clinvar	4 clinvar			36
start loss						0
frameshift	37 clinvar	19 clinvar	4 clinvar			60
splice donor/acceptor (+/-2bp)	10 clinvar	3 clinvar	14 clinvar			27
Total	70	44	460	124	2	700

Highest pathogenic variant AF is 0.0000014316474

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 213 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001348323.3	RefSeq	NP_001335252.1	41	MANE Select
ENST00000675903.1	Ensembl	ENSP00000502713.1	41	MANE Select
NM_001284214.2	RefSeq	NP_001271143.1	41	Standard
NM_001284215.2	RefSeq	NP_001271144.1	40	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation

Biological Process

protein polyubiquitination
DNA repair
ubiquitin-dependent protein catabolic process
cellular response to DNA damage stimulus
regulation of embryonic development

Molecular Function

ubiquitin-protein transferase activity
protein binding
thyroid hormone receptor binding

Cellular Component

nucleus
nucleoplasm
cytosol
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000283943
Coding exons: 40
Length: 159402
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125740
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.64	639	1.07e+3	0.600	0.0000566	12993
Missense (PolyPhen)		153	406.33	0.37654		4969
Synonymous	-0.763	402	383	1.05	0.0000205	3863
Loss of Function	9.34	2	106	0.0190	0.00000569	1297

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000061	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000068	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase involved in ubiquitin fusion degradation (UFD) pathway and regulation of DNA repair. Part of the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination of protein at their N-terminus, regardeless of the presence of lysine residues in target proteins. In normal cells, mediates ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A, a lysine-less tumor suppressor required for p53/TP53 activation under oncogenic stress. In cancer cells, however, isoform p19ARF/ARF and TRIP12 are located in different cell compartments, preventing isoform p19ARF/ARF ubiquitination and degradation. Does not mediate ubiquitination of isoform p16-INK4a of CDKN2A. Also catalyzes ubiquitination of NAE1 and SMARCE1, leading to their degradation. Ubiquitination and degradation of target proteins is regulated by interaction with proteins such as MYC, TRADD or SMARCC1, which disrupt the interaction between TRIP12 and target proteins. Acts as a key regulator of DNA damage response by acting as a suppressor of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites, thereby acting as a guard against excessive spreading of ubiquitinated chromatin at damaged chromosomes. {ECO:0000269|PubMed:18627766, ECO:0000269|PubMed:19028681, ECO:0000269|PubMed:20208519, ECO:0000269|PubMed:20829358, ECO:0000269|PubMed:22884692}.;
Disease: DISEASE: Mental retardation, autosomal dominant 49 (MRD49) [MIM:617752]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:27848077, ECO:0000269|PubMed:28251352}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.0453
RVIS EVS: -2.46
RVIS percentile EVS: 1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.630

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium