SLC40A1

solute carrier family 40 member 1, the group of Solute carrier family 40

Basic information

Region (hg38): 2:189560589-189583758

Previous symbols: [ "SLC11A3" ]

Links

ENSG00000138449 ∙ NCBI:30061 ∙ OMIM:604653 ∙ HGNC:10909 ∙ Uniprot:Q9NP59 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hemochromatosis type 4 (Strong), mode of inheritance: AD
• hemochromatosis type 4 (Strong), mode of inheritance: AD
• hemochromatosis type 4 (Supportive), mode of inheritance: AD
• hemochromatosis type 4 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemochromatosis, type 4	AD	Biochemical; Gastrointestinal; Hematologic	Phlebotomy may be beneficial in some individuals, but genetic diagnosis may be useful to direct treatment regimens, as some indviduals may have reduced tolerance to phlebotomy and can become anemic on therapy despite persistently elevated serum ferritin	Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic	1518736; 11431687; 14752817; 14757427; 15030991; 16351644; 15831700; 17566043; 17383046; 19709084; 19342478; 19589941; 20230395; 21175851; 21411349; 22584997; 22890139
Biallelic variants (with other hemochromatosis-related genes, such as HFE) have been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SLC40A1 gene.

• Hemochromatosis type 4 (165 variants)
• not provided (18 variants)
• Inborn genetic diseases (14 variants)
• Hereditary hemochromatosis (7 variants)
• not specified (5 variants)
• SLC40A1-related condition (5 variants)
• Hemochromatosis type 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SLC40A1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	36	6	43
missense	4	14	49	8	4	79
nonsense		2				2
start loss						0
frameshift			1			1
inframe indel		1	1	1		3
splice donor/acceptor (+/-2bp)			1			1
splice region			2	3	1	6
non coding			13	17	19	49
Total	4	17	66	62	29

Highest pathogenic variant AF is 0.00000657

Variants in SLC40A1

This is a list of pathogenic ClinVar variants found in the SLC40A1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-189560691-A-C		Hemochromatosis type 4	Uncertain significance (Jan 13, 2018)
2-189560748-T-C		Hemochromatosis type 4	Benign (Jan 12, 2018)
2-189560755-G-A		Hemochromatosis type 4	Benign (Jan 13, 2018)
2-189560878-T-A		Hemochromatosis type 4	Uncertain significance (Jan 12, 2018)
2-189561045-A-G		Hemochromatosis type 4	Benign (Jun 16, 2017)
2-189561142-C-CT		Hereditary hemochromatosis	Likely benign (Jun 14, 2016)
2-189561232-G-A		Hemochromatosis type 4	Uncertain significance (Jan 12, 2018)
2-189561456-CTA-C		Hereditary hemochromatosis	Uncertain significance (Jun 14, 2016)
2-189561569-C-T		Hemochromatosis type 4	Uncertain significance (Jan 12, 2018)
2-189561589-C-A		Hemochromatosis type 4	Benign (Jan 13, 2018)
2-189561750-T-C		Hemochromatosis type 4	Uncertain significance (Jan 12, 2018)
2-189561828-C-T		Hemochromatosis type 4	Benign (Jan 12, 2018)
2-189561913-T-C		Hemochromatosis type 4	Benign (Jan 24, 2024)
2-189561934-C-T		Inborn genetic diseases • Hemochromatosis type 4	Uncertain significance (Jan 07, 2022)
2-189561938-AGCAAAGAGC-A		SLC40A1-related disorder	Uncertain significance (Feb 28, 2024)
2-189561940-C-T		Hemochromatosis type 4	Benign (Jan 18, 2024)
2-189561988-T-A		Hemochromatosis type 4	Uncertain significance (Jan 28, 2022)
2-189561992-G-T		Hemochromatosis type 4	Likely benign (Jan 18, 2022)
2-189561995-C-A		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
2-189561997-T-C		Inborn genetic diseases	Uncertain significance (Jul 13, 2022)
2-189562002-A-G		Hemochromatosis type 4	Pathogenic (Mar 12, 2019)
2-189562006-A-G		Hemochromatosis type 4	Uncertain significance (Jan 06, 2023)
2-189562022-T-C		Hemochromatosis type 4	Likely benign (Nov 26, 2021)
2-189562024-C-T		Hemochromatosis type 4 • Inborn genetic diseases • SLC40A1-related disorder	Conflicting classifications of pathogenicity (Feb 14, 2023)
2-189562025-G-A		Hemochromatosis type 4	Benign/Likely benign (Jul 19, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SLC40A1	protein_coding	protein_coding	ENST00000261024	8	23180

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.988	0.0117	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.92	213	308	0.692	0.0000158	3698
Missense in Polyphen		33	93.106	0.35443		1174
Synonymous	1.17	100	116	0.862	0.00000635	1191
Loss of Function	4.25	3	26.7	0.113	0.00000167	271

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May be involved in iron export from duodenal epithelial cell and also in transfer of iron between maternal and fetal circulation. Mediates iron efflux in the presence of a ferroxidase (hephaestin and/or ceruloplasmin).
• Pathway: Mineral absorption - Homo sapiens (human);Ferroptosis - Homo sapiens (human);Iron metabolism in placenta;Transport of bile salts and organic acids, metal ions and amine compounds;SLC-mediated transmembrane transport;Transport of small molecules;Metal ion SLC transporters;Iron uptake and transport (Consensus)

Recessive Scores

• pRec: 0.258

Intolerance Scores

• loftool: 0.0890
• rvis_EVS: 0.33
• rvis_percentile_EVS: 73.41

Haploinsufficiency Scores

• pHI: 0.298
• hipred: Y
• hipred_score: 0.825
• ghis: 0.394

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.812

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Slc40a1
• Phenotype: immune system phenotype; renal/urinary system phenotype; skeleton phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: slc40a1
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: lymphocyte homeostasis;endothelium development;cellular iron ion homeostasis;regulation of transcription from RNA polymerase II promoter in response to iron;iron ion transmembrane transport;negative regulation of apoptotic process;positive regulation of transcription by RNA polymerase II;spleen trabecula formation;multicellular organismal iron ion homeostasis;divalent inorganic cation transport;iron ion export across plasma membrane
• Cellular component: nucleoplasm;cytoplasm;cytosol;plasma membrane;integral component of plasma membrane;synaptic vesicle;integral component of membrane;basolateral plasma membrane
• Molecular function: iron ion transmembrane transporter activity;protein binding;ferrous iron transmembrane transporter activity;peptide hormone binding;identical protein binding;iron channel activity