TGFBRAP1

protein-coding

transforming growth factor beta receptor associated protein 1, the group of CORVET complex

Gene summary

This gene encodes a protein that binds to transforming growth factor-beta (TGF-beta) receptors and plays a role in TGF-beta signaling. The encoded protein acts as a chaprone in signaling downstream of TGF-beta. It is involved in signal-dependent association with SMAD4. The protein is also a component of mammalian CORVET, a multisubunit tethering protein complex that is involved in fusion of early endosomes. [provided by RefSeq, Jun 2016]

MANE transcript

NM_004257.6

Inheritance

—

ClinVar variants

U:103B:14

Top phenotype

Long QT syndrome

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:105,264,391-105,329,735

External References & Databases

Ensembl (ENSG00000135966)

Transcript & Mutation Effects

hg38 • Region Span ~65.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TGFBRAP1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 102

not providedTotal: 7

Long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004257.6. 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	2 clinvar	4 clinvar	8
missense			98 clinvar	7 clinvar	1 clinvar	106
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	103	9	5	117

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004257.6	RefSeq	NP_004248.2	11	MANE Select
ENST00000393359.7	Ensembl	ENSP00000377027.2	11	MANE Select
NM_001142621.3	RefSeq	NP_001136093.1	11	Standard
NM_001328646.3	RefSeq	NP_001315575.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of cytoplasmic and nuclear SMAD2/3 signaling
TGF-beta receptor signaling

Biological Process

regulation of transcription, DNA-templated
intracellular protein transport
signal transduction
transforming growth factor beta receptor signaling pathway
endosome to lysosome transport

Molecular Function

transforming growth factor beta receptor binding
protein binding
SMAD binding

Cellular Component

early endosome
membrane
CORVET complex
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393359
Coding exons: 11
Length: 65621
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.36	426	513	0.831	0.0000314	5613
Missense (PolyPhen)		99	154.1	0.64243		1768
Synonymous	0.273	222	227	0.977	0.0000156	1726
Loss of Function	4.26	9	36.9	0.244	0.00000175	421

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling. May recruit SMAD4 to the vicinity of the receptor complex and facilitate its interaction with receptor-regulated Smads, such as SMAD2. {ECO:0000269|PubMed:11278302, ECO:0000269|PubMed:9545258}.;

Recessive Scores

pRec: 0.235

Intolerance Scores

LoFtool: 0.349
RVIS EVS: -1.04
RVIS percentile EVS: 7.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.650

Gene Damage Prediction

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