SLC39A8

protein-coding

solute carrier family 39 member 8, the group of Solute carrier family 39

Gene summary

This gene encodes a member of the SLC39 family of solute-carrier genes, which show structural characteristics of zinc transporters. The encoded protein is glycosylated and found in the plasma membrane and mitochondria, and functions in the cellular import of zinc at the onset of inflammation. It is also thought to be the primary transporter of the toxic cation cadmium, which is found in cigarette smoke. Multiple transcript variants encoding different isoforms have been found for this gene. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Oct 2008]

MANE transcript

NM_001135146.2

Inheritance

ClinVar variants

P:11U:125B:55

Top phenotype

Congenital disorder of glycosylation, type IIn

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr4:102,251,080-102,431,258

External References & Databases

Ensembl (ENSG00000138821)

Transcript & Mutation Effects

hg38 • Region Span ~180.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SLC39A8-CDGSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014746

Submitter: PanelApp Australia

SLC39A8-CDGSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014746

Submitter: Labcorp Genetics (formerly Invitae)

SLC39A8-CDGSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014746

Submitter: Orphanet

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SLC39A8 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The SLC39A8 gene encodes a transporter that functions in Mn, Zn, Cd, and Fe transport across the plasma membrane. Pathogenic variants in SLC39A8 have also been associated with a congenital disorder of glycosylation characterized by intellectual disability, developmental delay, cerebellar atrophy, and short stature (PMID: 26637978, 26637979). The only report of SLC39A8 gene in relation to autosomal recessive Leigh syndrome spectrum was in 2017 (PMID: 27995398). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one variant identified in one case in one publication (PMID: 27995398). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression, functional alterations in non-patient cells, and a model system (PMIDs: 25613900, 29453449, 22563477). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel June 8, 2020 (SOP Version 7).

SLC39A8-CDGDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014746

Submitter: G2P

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IInAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described with recurrent infections, and awareness may allow prompt management and prophylactic measures

Comments: Dietary galactose has been described as having biochemical but unclear clinical benefit

Refs: 26637978; 26637979

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC39A8 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 149

Inborn genetic diseasesTotal: 55

not specifiedTotal: 26

SLC39A8-CDGTotal: 24

SLC39A8-related disorderTotal: 11

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001135146.2. 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	44 clinvar		46
missense	1 clinvar	5 clinvar	94 clinvar	10 clinvar	1 clinvar	111
nonsense		4 clinvar	4 clinvar			8
start loss			1 clinvar			1
frameshift	1 clinvar		12 clinvar			13
splice donor/acceptor (+/-2bp)			12 clinvar			12
Total	2	9	125	54	1	191

Highest pathogenic variant AF is 0.000053408585

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001135146.2	RefSeq	NP_001128618.1	8	MANE Select
ENST00000356736.5	Ensembl	ENSP00000349174.4	8	MANE Select
NM_001135147.1	RefSeq	NP_001128619.1	10	Standard
NM_001135148.2	RefSeq	NP_001128620.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ferroptosis - Homo sapiens (human)
Nuclear Receptors Meta-Pathway
NRF2 pathway
Zinc homeostasis
Zinc influx into cells by the SLC39 gene family

Biological Process

zinc ion transport
cellular zinc ion homeostasis
cadmium ion transmembrane transport
zinc ion import across plasma membrane

Molecular Function

zinc ion transmembrane transporter activity

Cellular Component

plasma membrane
integral component of plasma membrane
organelle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394833
Coding exons: 8
Length: 180218
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125713
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.10	187	234	0.798	0.0000112	2982
Missense (PolyPhen)		52	94.066	0.55281		1210
Synonymous	1.20	79	93.7	0.843	0.00000487	938
Loss of Function	3.10	3	16.7	0.180	7.70e-7	223

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a manganese and zinc influx transporter (PubMed:12504855, PubMed:26637978). Plays a role in manganese reabsorption in the proximal tubule of the kidney and in manganese uptake into the brain (PubMed:26637978). {ECO:0000269|PubMed:12504855, ECO:0000305|PubMed:26637978}.;
Disease: DISEASE: Congenital disorder of glycosylation 2N (CDG2N) [MIM:616721]: A form of congenital disorder of glycosylation, a genetically heterogeneous group of autosomal recessive, multisystem disorders caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:26637978, ECO:0000269|PubMed:26637979}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.356
RVIS EVS: 0.17
RVIS percentile EVS: 65.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.589

Gene Damage Prediction

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