TRIP12

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

Basic information

Region (hg38): 2:229763836-229923239

Links

ENSG00000153827 ∙ NCBI:9320 ∙ OMIM:604506 ∙ HGNC:12306 ∙ Uniprot:Q14669 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Clark-Baraitser syndrome (Strong), mode of inheritance: AD
• syndromic intellectual disability (Supportive), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Clark-Baraitser syndrome	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	25363768; 27479843; 27848077; 28251352

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TRIP12 gene.

• not provided (175 variants)
• Clark-Baraitser syndrome (81 variants)
• Inborn genetic diseases (47 variants)
• TRIP12-related condition (10 variants)
• not specified (8 variants)
• Intellectual disability (6 variants)
• See cases (6 variants)
• Neurodevelopmental disorder (3 variants)
• TRIP12 associated autism with facial dysmorphology (1 variants)
• Developmental disorder (1 variants)
• Neurodevelopmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TRIP12 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				12	7	19
missense		5	157	13		175
nonsense	12	8	2			22
start loss						0
frameshift	25	6	1			32
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)	6	1	2			9
splice region	1	1	8	3	2	15
non coding			3		27	30
Total	43	21	167	25	34

Variants in TRIP12

This is a list of pathogenic ClinVar variants found in the TRIP12 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-229767552-G-A		TRIP12-related disorder	Benign (May 05, 2021)
2-229767574-G-A		Clark-Baraitser syndrome	Uncertain significance (May 02, 2018)
2-229767577-G-A			Likely pathogenic (Oct 23, 2020)
2-229767594-A-T		Inborn genetic diseases	Uncertain significance (Apr 21, 2022)
2-229767605-T-A		TRIP12-related disorder	Likely benign (Sep 08, 2022)
2-229767617-C-G		TRIP12-related disorder	Uncertain significance (Jan 10, 2024)
2-229767624-C-G		not specified	Uncertain significance (Jan 19, 2024)
2-229767629-A-C		Neurodevelopmental disorder	Likely pathogenic (Nov 22, 2022)
2-229767630-TAG-AA		Clark-Baraitser syndrome	Uncertain significance (Mar 07, 2023)
2-229767635-C-T		TRIP12-related disorder	Likely benign (Oct 28, 2019)
2-229767636-G-A		Clark-Baraitser syndrome	Likely pathogenic (Apr 03, 2020)
2-229767648-T-TAGTTCACACAAGTC		Clark-Baraitser syndrome	Likely pathogenic (Nov 10, 2021)
2-229767724-T-C		Clark-Baraitser syndrome	Uncertain significance (May 28, 2019)
2-229767726-A-C			Likely pathogenic (Feb 01, 2022)
2-229767742-T-C			Uncertain significance (Apr 04, 2023)
2-229767744-C-T		Inborn genetic diseases	Uncertain significance (Jun 21, 2022)
2-229767756-T-C		not specified	Uncertain significance (May 11, 2023)
2-229768616-C-T		Inborn genetic diseases	Uncertain significance (Sep 06, 2023)
2-229768672-T-A			Uncertain significance (Sep 18, 2019)
2-229768685-T-C		Clark-Baraitser syndrome	Uncertain significance (May 01, 2020)
2-229768687-C-T			Uncertain significance (Dec 05, 2019)
2-229768715-CCCG-AAGTAAATATACCATAT		Inborn genetic diseases	Pathogenic (Nov 03, 2021)
2-229768717-C-A			Uncertain significance (Apr 18, 2022)
2-229768722-A-G		TRIP12-related disorder	Benign (Feb 22, 2024)
2-229768856-T-TAAATC			Benign (May 17, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TRIP12	protein_coding	protein_coding	ENST00000283943	40	159402

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.52e-16	125733	0	7	125740	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.64	639	1.07e+3	0.600	0.0000566	12993
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000613	0.0000613
Ashkenazi Jewish	0.00	0.00
East Asian	0.000112	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000179	0.0000176
Middle Eastern	0.000112	0.0000544
South Asian	0.0000677	0.0000653
Other	0.00	0.00

dbNSFP

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

Recessive Scores

• pRec: 0.104

Intolerance Scores

• loftool: 0.0453
• rvis_EVS: -2.46
• rvis_percentile_EVS: 1

Haploinsufficiency Scores

• pHI: 0.887
• hipred: Y
• hipred_score: 0.783
• ghis: 0.621

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.630

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Trip12
• Phenotype: cellular phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; embryo phenotype

Gene ontology

• Biological process: protein polyubiquitination;DNA repair;ubiquitin-dependent protein catabolic process;cellular response to DNA damage stimulus;regulation of embryonic development;negative regulation of histone H2A K63-linked ubiquitination;negative regulation of double-strand break repair
• Cellular component: nucleus;nucleoplasm;cytosol;nuclear speck
• Molecular function: ubiquitin-protein transferase activity;protein binding;thyroid hormone receptor binding