TRAIP

protein-coding

TRAF interacting protein, the group of Ring finger proteins

Gene summary

This gene encodes a protein that contains an N-terminal RING finger motif and a putative coiled-coil domain. A similar murine protein interacts with TNFR-associated factor 1 (TRAF1), TNFR-associated factor 2 (TRAF2), and cylindromatosis. The interaction with TRAF2 inhibits TRAF2-mediated nuclear factor kappa-B, subunit 1 activation that is required for cell activation and protection against apoptosis. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005879.3

Inheritance

ClinVar variants

P:14U:89B:57

Top phenotype

Seckel syndrome 9

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr3:49,828,601-49,856,574

External References & Databases

Ensembl (ENSG00000183763)

Transcript & Mutation Effects

hg38 • Region Span ~28.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Seckel syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014767

Submitter: G2P

Seckel syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014767

Submitter: Labcorp Genetics (formerly Invitae)

Seckel syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014767

Submitter: PanelApp Australia

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

Clinical Genomic Database (CGD)

Seckel syndrome 9AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Pulmonary

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: 26595769

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAIP variants in ClinVar

5 Conditions Cataloged

not providedTotal: 146

Inborn genetic diseasesTotal: 65

Seckel syndrome 9Total: 13

TRAIP-related disorderTotal: 9

not specifiedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005879.3. 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			1 clinvar	45 clinvar	1 clinvar	47
missense	1 clinvar		79 clinvar	11 clinvar		91
nonsense	3 clinvar	1 clinvar	4 clinvar			8
start loss						0
frameshift	6 clinvar	1 clinvar	1 clinvar			8
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	10	4	89	56	1	160

Highest pathogenic variant AF is 0.00008921723

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005879.3	RefSeq	NP_005870.2	15	MANE Select
ENST00000331456.7	Ensembl	ENSP00000328203.2	15	MANE Select
ENST00000469027.5	Ensembl	ENSP00000420085.1	9	Standard
ENST00000469027.6	Ensembl	ENSP00000420085.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation

Biological Process

apoptotic process
signal transduction
cell population proliferation
negative regulation of tumor necrosis factor-mediated signaling pathway
protein ubiquitination

Molecular Function

protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

nucleolus
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331456
Coding exons: 15
Length: 27974
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.32	207	268	0.773	0.0000150	3069
Missense (PolyPhen)		48	76.122	0.63057		896
Synonymous	1.75	80	103	0.780	0.00000535	903
Loss of Function	2.79	13	29.3	0.443	0.00000151	330

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin ligase acting as a negative regulator of innate immune signaling. Inhibits activation of NF-kappa-B mediated by TNF. Negatively regulates TLR3/4- and RIG-I-mediated IRF3 activation and subsequent IFNB1 production and cellular antiviral response by promoting 'Lys-48'-linked polyubiquitination of TNK1 leading to its proteasomal degradation (By similarity) (PubMed:22945920). Involved in response to genotoxic lesions during genome replication. Promotes H2AX and RPA2 phosphorylation after replication-associated DNA damage and assists fork progression at UV-induced replication-blocking lesions during S phase (PubMed:26595769). Has also been proposed to play a role in promoting translesion synthesis by mediating the assembly of 'Lys- 63'-linked poly-ubiquitin chains on the Y-family polymerase POLN in order to facilitate bypass of DNA lesions and preserve genomic integrity (PubMed:24553286). The function in translesion synthesis is controversial (PubMed:26595769). {ECO:0000250|UniProtKB:Q8VIG6, ECO:0000269|PubMed:22945920, ECO:0000269|PubMed:24553286, ECO:0000269|PubMed:26595769, ECO:0000303|PubMed:26595769}.;
Disease: DISEASE: Seckel syndrome 9 (SCKL9) [MIM:616777]: A form of Seckel syndrome, a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:26595769}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0801

Intolerance Scores

LoFtool: 0.308
RVIS EVS: -0.36
RVIS percentile EVS: 29.16

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.885

Gene Damage Prediction

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