SLC39A14

protein-coding

solute carrier family 39 member 14, the group of Solute carrier family 39

Gene summary

This gene encodes a member of the the SLC39A family of divalent metal transporters that mediates the cellular uptake of manganese, zinc, iron, and cadmium. The encoded protein contains eight transmembrane domains, a histidine-rich motif, and a metalloprotease motif, and is expressed on the plasma membrane and the endocytic vesicle membrane. It is an important transporter of nontransferrin-bound iron and a critical regulator of manganese homeostasis. Naturally occurring mutations in this gene are associated with neurodegeneration with brain iron accumulation and early-onset parkinsonism-dystonia with hypermanganesemia. [provided by RefSeq, May 2017]

MANE transcript

NM_001128431.4

Inheritance

AR, AD

ClinVar variants

P:12U:95B:84

Top phenotype

Hyperostosis cranialis interna; Hypermanganesemia with dystonia 2

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr8:22,367,278-22,434,129

External References & Databases

Ensembl (ENSG00000104635)

Transcript & Mutation Effects

hg38 • Region Span ~66.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypermanganesemia with dystonia 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014864

Submitter: Orphanet

hypermanganesemia with dystonia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014864

Submitter: Labcorp Genetics (formerly Invitae)

hypermanganesemia with dystonia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014864

Submitter: G2P

hypermanganesemia with dystonia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014864

Submitter: PanelApp Australia

hyperostosis cranialis internaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007765

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hyperostosis cranialis interna; Hypermanganesemia with dystonia 2AD/AR

Manifestation: Biochemical; Musculoskeletal; Neurologic

Intervention: Biochemical; Musculoskeletal

Rationale: In Hyperostosis cranialis interna, surveillance for sequelae related to overgrowth, including hearing evaluation, assessment of signs of increased intracranial pressure and cranial nerve entrapment, can allow early surgical management; In Hypermanganesemia with dystonia 2, individuals have been described with childhood-onset neurodegenerative findings, and medical treatment (with early manganese chelation therapy) has been described as clinically beneficial

Refs: 20140965; 2300107; 27231142; 29621230

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC39A14 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 198

Inborn genetic diseasesTotal: 47

not specifiedTotal: 21

Hypermanganesemia with dystonia 2Total: 18

SLC39A14-related disorderTotal: 10

Hyperostosis cranialis internaTotal: 5

Congenital heart diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001128431.4. 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			2 clinvar	69 clinvar	5 clinvar	76
missense	5 clinvar	3 clinvar	88 clinvar	10 clinvar		106
nonsense	2 clinvar	1 clinvar	2 clinvar			5
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	7	5	95	79	5	191

Highest pathogenic variant AF is 0.000006569784

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 176 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001128431.4	RefSeq	NP_001121903.1	8	MANE Select
ENST00000381237.6	Ensembl	ENSP00000370635.1	8	MANE Select
NM_001135153.3	RefSeq	NP_001128625.1	8	Standard
NM_001135154.3	RefSeq	NP_001128626.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc39a14	Danio rerio	Structure: whole organism Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

slc39a14

Danio rerio

Structure: whole organism

Quality: decreased process quality

abnormal

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

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

Molecular Function

zinc ion transmembrane transporter activity
ferrous iron transmembrane transporter activity

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
integral component of membrane
lamellipodium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359741
Coding exons: 8
Length: 66881
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125747
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.92	194	285	0.680	0.0000162	3232
Missense (PolyPhen)		50	112.58	0.44413		1333
Synonymous	0.615	116	125	0.930	0.00000820	999
Loss of Function	2.97	5	19.0	0.264	8.09e-7	220

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00055	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Broad-scope metal ion transporter with a preference for zinc uptake (PubMed:29621230). Also mediates cellular uptake of nontransferrin-bound iron. {ECO:0000269|PubMed:15642354, ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:29621230}.;
Disease: DISEASE: Hyperostosis cranialis interna (HCIN) [MIM:144755]: An autosomal dominant bone disorder characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base. The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting during the second decade of life. {ECO:0000269|PubMed:29621230}. Note=The disease is caused by mutations affecting the gene represented in this entry. Conditional knockin mice overexpressing Arg-438 variant, which is the mouse equivalent of human variant Leu-441, in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. {ECO:0000269|PubMed:29621230}.;

Recessive Scores

pRec: 0.153

Intolerance Scores

LoFtool: 0.544
RVIS EVS: -0.42
RVIS percentile EVS: 25.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.636

Gene Damage Prediction

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