TMX3

protein-coding

thioredoxin related transmembrane protein 3, the group of Protein disulfide isomerases|Thioredoxin domain containing

Gene summary

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The canonical protein encoded by this gene has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This gene is expressed in many tissues but has its highest expression in heart and skeletal muscle. It is expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye and haploinsufficiency of this gene in humans and zebrafish is associated with microphthalmia. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

Previous symbols:

TXNDC10

MANE transcript

NM_019022.5

Inheritance

—

ClinVar variants

U:48B:4

Top phenotype

TMX3-related disorder

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr18:68,673,688-68,715,108

External References & Databases

Ensembl (ENSG00000166479)

Transcript & Mutation Effects

hg38 • Region Span ~41.4 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 TMX3 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 39

not providedTotal: 15

TMX3-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019022.5. 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
missense			42 clinvar	3 clinvar	1 clinvar	46
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	48	3	1	52

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019022.5	RefSeq	NP_061895.3	16	MANE Select
ENST00000299608.7	Ensembl	ENSP00000299608.2	16	MANE Select
NM_001350512.2	RefSeq	NP_001337441.1	8	Standard
NM_001350513.2	RefSeq	NP_001337442.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tmx3a	Danio rerio	Structure: eye Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

tmx3a

Danio rerio

Structure: eye

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet degranulation
Response to elevated platelet cytosolic Ca2+
Platelet activation, signaling and aggregation
Hemostasis

Biological Process

platelet degranulation
peptidyl-cysteine oxidation
cell redox homeostasis

Molecular Function

protein disulfide isomerase activity
protein binding
thiol oxidase activity

Cellular Component

endoplasmic reticulum membrane
plasma membrane
cell surface
integral component of membrane
platelet alpha granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299608
Coding exons: 16
Length: 41611
Individuals with no LoFs: 125703
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125726
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	173	223	0.776	0.0000102	2966
Missense (PolyPhen)		58	87.113	0.6658		1205
Synonymous	-0.00634	75	74.9	1.00	0.00000348	796
Loss of Function	3.18	9	26.7	0.337	0.00000134	347

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00012	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00010	0.000097	rare
South Asian	0.000072	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable disulfide isomerase, which participates in the folding of proteins containing disulfide bonds. May act as a dithiol oxidase. {ECO:0000269|PubMed:15623505}.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.726
RVIS EVS: 0.24
RVIS percentile EVS: 69.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.602

Gene Damage Prediction

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