SLC4A1

solute carrier family 4 member 1 (Diego blood group), the group of Blood group antigens|CD molecules|Solute carrier family 4

Basic information

Region (hg38): 17:44248390-44268141

Previous symbols: [ "EPB3", "AE1", "DI", "WD" ]

Links

ENSG00000004939 ∙ NCBI:6521 ∙ OMIM:109270 ∙ HGNC:11027 ∙ Uniprot:P02730 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spherocytosis (Supportive), mode of inheritance: AD
• dehydrated hereditary stomatocytosis (Supportive), mode of inheritance: AD
• autosomal dominant distal renal tubular acidosis (Supportive), mode of inheritance: AD
• renal tubular acidosis, distal, 4, with hemolytic anemia (Supportive), mode of inheritance: AD
• southeast Asian ovalocytosis (Supportive), mode of inheritance: AD
• cryohydrocytosis (Supportive), mode of inheritance: AD
• renal tubular acidosis, distal, 4, with hemolytic anemia (Strong), mode of inheritance: AR
• autosomal dominant distal renal tubular acidosis (Strong), mode of inheritance: AD
• renal tubular acidosis, distal, 4, with hemolytic anemia (Strong), mode of inheritance: AR
• southeast Asian ovalocytosis (Strong), mode of inheritance: AD
• cryohydrocytosis (Limited), mode of inheritance: Unknown
• hereditary spherocytosis type 4 (Strong), mode of inheritance: AD
• autosomal dominant distal renal tubular acidosis (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spherocytosis, type 4; Ovalcytosis, Southeast Asian; Cryohydrocytosis; Renal tubular acidosis, distal, with hemolytic anemia; Renal tubular acidosis, distal, 1; Renal tubular acidosis, distal, autosomal recessive; Blood group, Wright; Blood group, Waldner; Blood group, Diego; Blood group, Froese; Blood group, Swann	AD/AR/BG	Hematologic; Renal	In Renal tubular acidosis, if detected early, therapeutic correction of the acidosis by alkali administration leads in most cases to improvement of biochemical abnormalities and resumption of normal growth, as well as beneficial regarding skeletal manifestations; As pertains to hematologic manifestations, splenectomy has been reported as being beneficial; Variants associated with a blood group may be important in specific situations (eg, related to transfusion)	Hematologic; Renal	13288586; 13669428; 13739450; 6025225; 2829189; 2146504; 1824272; 1536803; 1519367; 1737855; 1520883; 8343110; 7713501; 8206915; 8282779; 7919393; 7812009; 8547122; 8704215; 8608262; 8567957; 9207478; 9312167; 9734643; 9973643; 9600966; 9854053; 10403343; 10926824; 11061863; 10942416; 11155072; 11380459; 11756190; 12087557; 15211439; 16227998; 19229254; 19297287; 20015879; 20799361; 20825599; 20960171; 22126643; 22609520; 22693689; 22919024; 23255290; 23498825; 23878048; 24257694

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SLC4A1 gene.

• not provided (38 variants)
• Hereditary spherocytosis type 4 (8 variants)
• Autosomal dominant distal renal tubular acidosis (3 variants)
• not specified (2 variants)
• SLC4A1-related disorder (2 variants)
• Distal renal tubular acidosis (1 variants)
• Southeast Asian ovalocytosis (1 variants)
• 11 conditions (1 variants)
• Renal tubular acidosis, distal, 4, with hemolytic anemia (1 variants)
• Inborn genetic diseases (1 variants)
• Renal tubular acidosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SLC4A1 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			5	65	10	80
missense	7	20	204	13	2	246
nonsense	13	14	1			28
start loss						0
frameshift	20	30	3			53
inframe indel		2	6			8
splice donor/acceptor (+/-2bp)	6	13				19
splice region		1	14	8		23
non coding			43	54	30	127
Total	46	79	262	132	42

Highest pathogenic variant AF is 0.0000394

Variants in SLC4A1

This is a list of pathogenic ClinVar variants found in the SLC4A1 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-44248525-C-T		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Benign/Likely benign (Jan 13, 2018)
17-44248626-C-T		Hemolytic anemia • Autosomal dominant distal renal tubular acidosis • Hereditary spherocytosis type 4	Uncertain significance (Jan 12, 2018)
17-44248666-C-T		Autosomal dominant distal renal tubular acidosis • Hemolytic anemia • Hereditary spherocytosis type 4	Benign/Likely benign (Jan 12, 2018)
17-44248667-G-A		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Uncertain significance (Jan 12, 2018)
17-44248692-G-A		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Uncertain significance (Jan 12, 2018)
17-44248737-C-T		Autosomal dominant distal renal tubular acidosis • Hemolytic anemia • Hereditary spherocytosis type 4	Benign (Jan 13, 2018)
17-44248765-C-T		Autosomal dominant distal renal tubular acidosis • Hereditary spherocytosis type 4 • Hemolytic anemia	Uncertain significance (Jan 13, 2018)
17-44248782-T-C		Hereditary spherocytosis type 4 • Hemolytic anemia • Autosomal dominant distal renal tubular acidosis	Uncertain significance (Jan 13, 2018)
17-44248849-G-A		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Uncertain significance (Jan 13, 2018)
17-44248849-GT-G		Distal Renal Tubular Acidosis, Dominant • Hemolytic anemia • Spherocytosis, Dominant	Uncertain significance (Jun 14, 2016)
17-44248849-G-GT		Distal Renal Tubular Acidosis, Dominant • Spherocytosis, Dominant • Hemolytic anemia	Uncertain significance (Jun 14, 2016)
17-44248849-G-GTTT		Spherocytosis, Dominant • Distal Renal Tubular Acidosis, Dominant • Hemolytic anemia	Uncertain significance (Jun 14, 2016)
17-44248862-T-G		Hereditary spherocytosis type 4 • Hemolytic anemia • Autosomal dominant distal renal tubular acidosis	Uncertain significance (Jan 12, 2018)
17-44248890-C-T		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Benign (Jan 12, 2018)
17-44249049-A-G		Autosomal dominant distal renal tubular acidosis • Hemolytic anemia • Hereditary spherocytosis type 4	Uncertain significance (Jan 12, 2018)
17-44249065-T-A		Hereditary spherocytosis type 4 • Hemolytic anemia • Autosomal dominant distal renal tubular acidosis	Conflicting classifications of pathogenicity (Jan 13, 2018)
17-44249142-G-A		Hemolytic anemia • Autosomal dominant distal renal tubular acidosis • Hereditary spherocytosis type 4	Uncertain significance (Jan 13, 2018)
17-44249153-C-T		Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis • Hemolytic anemia	Uncertain significance (Jan 12, 2018)
17-44249184-TC-T		Spherocytosis, Dominant • Hemolytic anemia • Distal Renal Tubular Acidosis, Dominant	Uncertain significance (Jun 14, 2016)
17-44249185-C-A		Hemolytic anemia • Autosomal dominant distal renal tubular acidosis • Hereditary spherocytosis type 4	Uncertain significance (Jan 12, 2018)
17-44249221-G-A		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Benign/Likely benign (Jan 12, 2018)
17-44249231-T-G		Autosomal dominant distal renal tubular acidosis • Hemolytic anemia • Hereditary spherocytosis type 4	Benign/Likely benign (Jan 12, 2018)
17-44249260-T-A		Hemolytic anemia • Autosomal dominant distal renal tubular acidosis • Hereditary spherocytosis type 4	Uncertain significance (Jan 13, 2018)
17-44249354-AT-A		Spherocytosis, Dominant • Distal Renal Tubular Acidosis, Dominant • Hemolytic anemia	Likely benign (Jun 14, 2016)
17-44249411-A-G		Hemolytic anemia • Hereditary spherocytosis type 4 • Autosomal dominant distal renal tubular acidosis	Uncertain significance (Apr 27, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SLC4A1	protein_coding	protein_coding	ENST00000262418	19	19757

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.846	0.154	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.66	426	534	0.798	0.0000353	5848
Missense in Polyphen		162	231.02	0.70124		2545
Synonymous	-0.575	241	230	1.05	0.0000155	1935
Loss of Function	4.81	8	41.4	0.193	0.00000214	456

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000904	0.0000904
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000534	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Major integral membrane glycoprotein of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine. {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:14734552, ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:20151848, ECO:0000269|PubMed:24121512}.
• Disease: DISEASE: Ovalocytosis, Southeast Asian (SAO) [MIM:166900]: A hereditary hematologic disorder characterized by ovalocytic erythrocytes that are rigid and exhibit reduced expression of many erythrocyte antigens. Clinical manifestations include mild hemolysis, intermittent jaundice and gallstones. However, the disorder is most often asymptomatic. {ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:1722314}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spherocytosis 4 (SPH4) [MIM:612653]: Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. {ECO:0000269|PubMed:10580570, ECO:0000269|PubMed:10745622, ECO:0000269|PubMed:10942416, ECO:0000269|PubMed:11380459, ECO:0000269|PubMed:1378323, ECO:0000269|PubMed:15813913, ECO:0000269|PubMed:16227998, ECO:0000269|PubMed:7530501, ECO:0000269|PubMed:8547122, ECO:0000269|PubMed:8640229, ECO:0000269|PubMed:8943874, ECO:0000269|PubMed:9012689, ECO:0000269|PubMed:9207478, ECO:0000269|PubMed:9233560, ECO:0000269|PubMed:9973643}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal tubular acidosis, distal, autosomal dominant (AD- dRTA) [MIM:179800]: An autosomal dominant disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha- intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal tubular acidosis, distal, with hemolytic anemia (dRTA-HA) [MIM:611590]: A disease characterized by the association of hemolytic anemia with distal renal tubular acidosis, the reduced ability to acidify urine resulting in variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:15211439, ECO:0000269|PubMed:9854053}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Renal tubular acidosis, distal, with normal red cell morphology (dRTA-NRC) [MIM:611590]: A disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha- intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. {ECO:0000269|PubMed:15211439}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cryohydrocytosis (CHC) [MIM:185020]: An autosomal dominant disorder of red cell membrane permeability characterized by cold-induced changes in cell volume, resulting in cold- sensitive stomatocytosis, and increased erythrocyte osmotic fragility and autohemolysis at 4 degrees Celsius. Patients present with mild to moderate hemolytic anemia, splenomegaly, fatigue, and pseudohyperkalemia due to a potassium leak from the erythrocytes. {ECO:0000269|PubMed:16227998}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.
• Pathway: Collecting duct acid secretion - Homo sapiens (human);O2/CO2 exchange in erythrocytes;Transport of inorganic cations/anions and amino acids/oligopeptides;SLC-mediated transmembrane transport;Transport of small molecules;Erythrocytes take up oxygen and release carbon dioxide;Bicarbonate transporters;Erythrocytes take up carbon dioxide and release oxygen (Consensus)

Recessive Scores

• pRec: 0.577

Intolerance Scores

• loftool: 0.160
• rvis_EVS: -0.79
• rvis_percentile_EVS: 12.62

Haploinsufficiency Scores

• pHI: 0.110
• hipred: Y
• hipred_score: 0.602
• ghis: 0.671

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.917

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Slc4a1
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; hematopoietic system 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); 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); 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); renal/urinary system phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: slc4a1b
• Affected structure: neuromast hair cell
• Phenotype tag: abnormal
• Phenotype quality: decreased efficacy

Gene ontology

• Biological process: anion transport;chloride transport;cellular ion homeostasis;bicarbonate transport;regulation of intracellular pH;chloride transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;integral component of membrane;basolateral plasma membrane;Z disc;cortical cytoskeleton;extracellular exosome;blood microparticle
• Molecular function: inorganic anion exchanger activity;protein binding;anion transmembrane transporter activity;bicarbonate transmembrane transporter activity;chloride transmembrane transporter activity;anion:anion antiporter activity;ankyrin binding;protein homodimerization activity;protein membrane anchor