GET3

protein-coding

guided entry of tail-anchored proteins factor 3, ATPase, the group of Guided entry of tail-anchored proteins complex subunits|GET4-GET5 transmembrane domain recognition complex subunits

Gene summary

This gene represents the human homolog of the bacterial arsA gene, encoding the arsenite-stimulated ATPase component of the arsenite transporter responsible for resistance to arsenicals. This protein is also a central component of a transmembrane domain (TMD) recognition complex (TRC) that is involved in the post-translational delivery of tail-anchored (TA) proteins from the cytosol to the endoplasmic reticulum (ER). It recognizes and selectively binds the TMD of TA proteins in the cytosol, and delivers them to the ER for insertion. [provided by RefSeq, Oct 2011]

Previous symbols:

ASNA1

MANE transcript

NM_004317.4

Inheritance

ClinVar variants

P:1U:38B:1

Top phenotype

Cardiomyopathy, dilated, 2H

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr19:12,737,139-12,748,323

External References & Databases

Ensembl (ENSG00000198356)

Transcript & Mutation Effects

hg38 • Region Span ~11.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiomyopathy, dilated, 2HLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859358

Submitter: ClinGen

GET3 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). GET3 is a cytosolic chaperone that mediates insertion of TA (tail-anchored) proteins into the endoplasmic reticulum (ER) membrane. Homozygous KO mice were embryonic lethal, whereas heterozygous mice did not exhibit a phenotype. Two siblings affected with childhood onset, quickly progressing dilated cardiomyopathy had compound heterozygous variants in GET3 that segregated with disease. GET3 expression in both patients’ samples was markedly reduced compared to controls. GET3 KO zebrafish showed abnormal cardiac contractions and decreased blood flow, thinner walls and less organized Z-lines with irregular intercalated discs compared to heterozygous clutchmates. None of the homozygous fish survived past 8dpf. Injection of wild-type human GET mRNA into GET3 KO zebrafish embryos significantly rescued the phenotype, whereas injection with either mutant mRNA had no significant effect. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of GET3 with AR DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 07/26/2024 (SOP Version 10)

acute proliferative glomerulonephritisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0001644

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 2HAR

Manifestation: Cardiovascular

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: 31461301

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GET3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 30

not providedTotal: 1

Prostate cancerTotal: 1

Cardiomyopathy, dilated, 2HTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004317.4. 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		1
missense	1 clinvar		33 clinvar			34
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	1	0	38	1	0	40

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004317.4	RefSeq	NP_004308.2	7	MANE Select
ENST00000357332.8	Ensembl	ENSP00000349887.3	7	MANE Select
NM_001371488.1	RefSeq	NP_001358417.1	7	Standard
NM_001371489.1	RefSeq	NP_001358418.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
asna1	Danio rerio	Structure: retinal outer plexiform layer Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

asna1

Danio rerio

Structure: retinal outer plexiform layer

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

XBP1(S) activates chaperone genes
IRE1alpha activates chaperones
Unfolded Protein Response (UPR)
Metabolism of proteins

Biological Process

posttranslational protein targeting to endoplasmic reticulum membrane
arsenite transport
IRE1-mediated unfolded protein response
tail-anchored membrane protein insertion into ER membrane

Molecular Function

transporter activity
protein binding
ATP binding
arsenite transmembrane transporter activity
ATPase activity

Cellular Component

nucleus
nucleolus
cytoplasm
endoplasmic reticulum membrane
GET complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000591090
Coding exons: 7
Length: 11185
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125744
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	120	210	0.571	0.0000119	2307
Missense (PolyPhen)		15	65.723	0.22823		782
Synonymous	-0.801	100	90.3	1.11	0.00000575	670
Loss of Function	3.15	1	13.5	0.0742	5.70e-7	167

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors, where the tail- anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dimer state, facilitating recognition of newly synthesized TA membrane proteins. ATP hydrolysis is required for insertion. Subsequently, the homodimer reverts towards the open dimer state, lowering its affinity for the membrane-bound receptor, and returning it to the cytosol to initiate a new round of targeting (By similarity). May be involved in insulin signaling. {ECO:0000255|HAMAP-Rule:MF_03112, ECO:0000269|PubMed:17382883, ECO:0000269|PubMed:18477612, ECO:0000269|PubMed:25535373}.;

Recessive Scores

pRec: 0.178

Intolerance Scores

LoFtool: 0.361
RVIS EVS: -0.54
RVIS percentile EVS: 20.26

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.963

Gene Damage Prediction

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