SLC4A4

solute carrier family 4 member 4, the group of Solute carrier family 4

Basic information

Region (hg38): 4:71062667-71572087

Previous symbols: [ "SLC4A5" ]

Links

ENSG00000080493

∙ NCBI:8671 ∙ OMIM:603345 ∙ HGNC:11030 ∙ Uniprot:Q9Y6R1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

autosomal recessive proximal renal tubular acidosis (Definitive), mode of inheritance: AR
autosomal recessive proximal renal tubular acidosis (Strong), mode of inheritance: AR
autosomal recessive proximal renal tubular acidosis (Supportive), mode of inheritance: AR
autosomal recessive proximal renal tubular acidosis (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Renal tubular acidosis, proximal, with ocular abnormalities and impaired intellectual development	AD/AR	Ophthalmologic; Renal	Medical treatment of renal tubular acidosis may be beneficial; Diagnosis may allow early treatment related to ocular anomalies, which can include glaucoma	Dental; Neurologic; Ophthalmologic; Renal	8142230; 10545938; 11274232; 20798035
Heterozygous variants may result in ophthalmologic anomalies (including glaucoma) and migraine susceptibility

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SLC4A4 gene.

Autosomal_recessive_proximal_renal_tubular_acidosis (161 variants)
not_provided (150 variants)
Inborn_genetic_diseases (81 variants)
SLC4A4-related_disorder (14 variants)
not_specified (2 variants)
Combined_oxidative_phosphorylation_defect_type_24 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SLC4A4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001098484.3. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			12 clinvar	61 clinvar	3 clinvar	76
missense	2 clinvar	4 clinvar	142 clinvar	12 clinvar	1 clinvar	161
nonsense	1 clinvar	2 clinvar				3
start loss						0
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)		1 clinvar		1 clinvar		2
Total	5	8	155	74	4

Highest pathogenic variant AF is 0.00000342297

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SLC4A4	protein_coding	protein_coding	ENST00000425175	24	384802

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00278	125732	0	12	125744	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.14	367	580	0.633	0.0000305	7245
Missense in Polyphen		98	243.59	0.40231		3003
Synonymous	0.153	210	213	0.987	0.0000118	2090
Loss of Function	5.49	7	48.1	0.145	0.00000232	612

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000124	0.000123
Ashkenazi Jewish	0.0000996	0.0000992
East Asian	0.00	0.00
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.0000531	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

Function: FUNCTION: Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH. {ECO:0000269|PubMed:10069984, ECO:0000269|PubMed:12907161, ECO:0000269|PubMed:16636648, ECO:0000269|PubMed:16769890, ECO:0000269|PubMed:17661077, ECO:0000269|PubMed:29500354, ECO:0000269|PubMed:9235899, ECO:0000269|PubMed:9651366}.;
Disease: DISEASE: Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA) [MIM:604278]: An extremely rare autosomal recessive syndrome characterized by short stature, profound proximal renal tubular acidosis, mental retardation, bilateral glaucoma, cataracts and bandkeratopathy. pRTA is due to a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. {ECO:0000269|PubMed:10545938, ECO:0000269|PubMed:15471865, ECO:0000269|PubMed:15713912, ECO:0000269|PubMed:15930088, ECO:0000269|PubMed:16636648, ECO:0000269|PubMed:17661077}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Loss of interaction with and stimulation by CA4 is the cause of retinitis pigmentosa type 17 (RP17).;
Pathway: Bile secretion - Homo sapiens (human);Proximal tubule bicarbonate reclamation - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Transport of inorganic cations/anions and amino acids/oligopeptides;SLC-mediated transmembrane transport;Transport of small molecules;Bicarbonate transporters (Consensus)

Recessive Scores

pRec: 0.321

Intolerance Scores

loftool: 0.0198
rvis_EVS: -0.37
rvis_percentile_EVS: 28.2

Haploinsufficiency Scores

pHI: 0.0630
hipred: Y
hipred_score: 0.728
ghis: 0.402

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.740

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Slc4a4
Phenotype: muscle phenotype; craniofacial phenotype; homeostasis/metabolism 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); 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); digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton 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);

Zebrafish Information Network

Gene name: slc4a4a
Affected structure: retina
Phenotype tag: abnormal
Phenotype quality: distended

Gene ontology

Biological process: sodium ion transport;inorganic anion transport;bicarbonate transport;regulation of intracellular pH;anion transmembrane transport
Cellular component: plasma membrane;integral component of plasma membrane;basolateral plasma membrane;extracellular exosome
Molecular function: inorganic anion exchanger activity;protein binding;sodium:bicarbonate symporter activity