SLC39A7

protein-coding

solute carrier family 39 member 7, the group of Solute carrier family 39

Gene summary

The protein encoded by this gene transports zinc from the Golgi and endoplasmic reticulum to the cytoplasm. This transport may be important for activation of tyrosine kinases, some of which could be involved in cancer progression. Therefore, modulation of the encoded protein could be useful as a therapeutic agent against cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Previous symbols:

HKE4

MANE transcript

NM_006979.3

Inheritance

ClinVar variants

P:6U:124B:82

Top phenotype

Agammaglobulinemia 9, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr6:33,200,305-33,204,439

External References & Databases

Ensembl (ENSG00000112473)

Transcript & Mutation Effects

hg38 • Region Span ~4.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

agammaglobulinemia 9, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030519

Submitter: PanelApp Australia

agammaglobulinemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0015977

Submitter: ClinGen

SLC39A7 was first reported in relation to autosomal recessive agammaglobulinemia in 2019 (Anzilotti C, et al., 2019, PMID: 30718914). Hypomorphic mutations in the SLC39A7 gene, encoding ZIP7, cause a human immunodeficiency syndrome characterized by an absence of circulating B cells, agammaglobulinemia and early-onset infections. Seven missense variants have been reported in five probands, and one additional family member, in one publication (PMID: 30718914). This gene-disease association is supported by its function as a zinc transporter (PMID: 14525538) that contributes to proper signal transduction through the (pre-)BCR for the transition from pre-B cell to immature B cell. Functional alteration is found in patient cells in which constitutive phosphatase activity was indeed higher (PMID: 30718914). Additionally, there is a knock-in mouse model that recapitulates disease (PMID: 30718914). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

agammaglobulinemia 9, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030519

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Agammaglobulinemia 9, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious; Dermatologic

Intervention: Allergy/Immunology/Infectious

Rationale: The condition can involve immunologic dysfunction, including with recurrent bacterial infections, and early diagnosis can allow management (eg, with IVIG); HSCT has been described

Refs: 30718914

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC39A7 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 219

not specifiedTotal: 71

Agammaglobulinemia 9, autosomal recessiveTotal: 9

SLC39A7-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006979.3. 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			4 clinvar	68 clinvar	3 clinvar	75
missense	3 clinvar		111 clinvar	10 clinvar	1 clinvar	125
nonsense		3 clinvar	3 clinvar			6
start loss						0
frameshift			6 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	3	3	124	78	4	212

Highest pathogenic variant AF is 0.00005329521

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006979.3	RefSeq	NP_008910.2	7	MANE Select
ENST00000374677.8	Ensembl	ENSP00000363809.3	7	MANE Select
NM_001077516.2	RefSeq	NP_001070984.1	7	Standard
NM_001288777.2	RefSeq	NP_001275706.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc39a7	Danio rerio	Structure: whole organism Quality: dead abnormal

Gene / Model

Organism

Observed Phenotype

slc39a7

Danio rerio

Structure: whole organism

Quality: dead

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nuclear Receptors Meta-Pathway
NRF2 pathway
Zinc homeostasis
Zinc influx into cells by the SLC39 gene family
Transport of bile salts and organic acids, metal ions and amine compounds

Biological Process

cellular zinc ion homeostasis
zinc ion transmembrane transport

Molecular Function

zinc ion transmembrane transporter activity
protein binding

Cellular Component

nucleoplasm
endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374677
Coding exons: 7
Length: 3995
Individuals with no LoFs: 124765
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 124798
p: 0.000132

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.53	198	269	0.737	0.0000141	3020
Missense (PolyPhen)		52	84.666	0.61418		980
Synonymous	2.38	77	109	0.709	0.00000579	1011
Loss of Function	2.72	5	17.1	0.292	7.96e-7	206

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.00013	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00017	0.00016	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Zinc transporter, that transports Zn(2+) from the endoplasmic reticulum/Golgi apparatus to the cytosol. Transport is stimulated by growth factors, such as EGF, and Ca(2+), as well as by exogenous Zn(2+). {ECO:0000269|PubMed:14525538, ECO:0000269|PubMed:15705588, ECO:0000269|PubMed:22317921}.;

Intolerance Scores

LoFtool: 0.828
RVIS EVS: 0.04
RVIS percentile EVS: 57.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.968

Gene Damage Prediction

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