TRAP1

protein-coding

TNF receptor associated protein 1, the group of Heat shock 90kDa proteins

Gene summary

This gene encodes a mitochondrial chaperone protein that is member of the heat shock protein 90 (HSP90) family. The encoded protein has ATPase activity and interacts with tumor necrosis factor type I. This protein may function in regulating cellular stress responses. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

MANE transcript

NM_016292.3

Inheritance

ClinVar variants

P:1U:302B:105

Top phenotype

Congenital abnormalities of the kidney and urinary tract; VACTERL association

gnomAD constraint

pLI —, LoF o/e 1.09

Max pathogenic AF

—

Genomic locus

chr16:3,651,639-3,717,553

External References & Databases

Ensembl (ENSG00000126602)

Transcript & Mutation Effects

hg38 • Region Span ~65.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Congenital abnormalities of the kidney and urinary tract; VACTERL associationAR

Manifestation: Cardiovascular; Gastrointestinal; Genitourinary; Musculoskeletal; Renal

Intervention: Cardiovascular; Renal

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management; Monitoring and intervention related to vesicoureteral reflux may be beneficial in terms of helping to preserve renal function

Refs: 24152966

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAP1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 333

not specifiedTotal: 209

TRAP1-related disorderTotal: 47

Congenital anomaly of kidney and urinary tractTotal: 1

Hereditary renal cell carcinomaTotal: 1

HER2 positive breast carcinomaTotal: 1

VATER associationTotal: 1

Congenital anomalies of kidney and urinary tract 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016292.3. 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			2 clinvar	76 clinvar	3 clinvar	81
missense			274 clinvar	22 clinvar	4 clinvar	300
nonsense	1 clinvar		7 clinvar			8
start loss			2 clinvar			2
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	1	0	302	98	7	408

Highest pathogenic variant AF is 6.855457e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016292.3	RefSeq	NP_057376.2	18	MANE Select
ENST00000246957.10	Ensembl	ENSP00000246957.5	18	MANE Select
NM_001272049.2	RefSeq	NP_001258978.1	17	Standard
ENST00000538171.5	Ensembl	ENSP00000442070.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TNF alpha Signaling Pathway
TGF-beta Signaling Pathway
Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism

Biological Process

translational attenuation
chaperone-mediated protein folding
negative regulation of cellular respiration
negative regulation of reactive oxygen species biosynthetic process
negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide

Molecular Function

RNA binding
tumor necrosis factor receptor binding
protein binding
ATP binding
protein kinase binding

Cellular Component

nucleoplasm
mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246957
Coding exons: 18
Length: 65959
Individuals with no LoFs: 125557
Homozygous LoFs: 0
Heterozygous LoFs: 191
Defined: 125748
p: 0.000760

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.72	587	428	1.37	0.0000283	4533
Missense (PolyPhen)		257	185.01	1.3891		1868
Synonymous	-4.33	255	181	1.41	0.0000129	1397
Loss of Function	-0.526	42	38.5	1.09	0.00000205	439

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00066	0.00065	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00078	0.00076	rare
South Asian	0.0014	0.0014	notable
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA. {ECO:0000269|PubMed:23525905, ECO:0000269|PubMed:23564345, ECO:0000269|PubMed:23747254}.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.927
RVIS EVS: -0.34
RVIS percentile EVS: 30.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.819

Gene Damage Prediction

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