AKR1C4

aldo-keto reductase family 1 member C4, the group of Aldo-keto reductases

Basic information

Region (hg38): 10:5195462-5218949

Previous symbols: [ "CHDR" ]

Links

ENSG00000198610 ∙ NCBI:1109 ∙ OMIM:600451 ∙ HGNC:387 ∙ Uniprot:P17516 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency (Limited), mode of inheritance: AR

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AKR1C4 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AKR1C4 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				10	1	11
missense			29	6	5	40
nonsense			1			1
start loss						0
frameshift						0
inframe indel				1		1
splice donor/acceptor (+/-2bp)						0
splice region			2	3		5
non coding				4	2	6
Total	0	0	30	21	8

Variants in AKR1C4

This is a list of pathogenic ClinVar variants found in the AKR1C4 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-5196852-AAAG-A		AKR1C4-related disorder	Likely benign (Sep 23, 2024)
10-5196885-G-A		AKR1C4-related disorder	Likely benign (Apr 06, 2022)
10-5196886-C-T		AKR1C4-related disorder	Uncertain significance (Feb 21, 2022)
10-5196909-C-G		AKR1C4-related disorder	Likely benign (May 31, 2023)
10-5196915-G-A		AKR1C4-related disorder	Uncertain significance (Jul 10, 2024)
10-5196919-G-A			Uncertain significance (Sep 10, 2023)
10-5200066-TGAA-T		AKR1C4-related disorder	Likely benign (Aug 06, 2024)
10-5200075-G-T		46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	risk factor (Aug 12, 2011)
10-5200078-C-T		AKR1C4-related disorder	Likely benign (Dec 09, 2022)
10-5200083-C-G		AKR1C4-related disorder	Likely benign (Feb 13, 2024)
10-5200170-T-G			Likely benign (Jan 12, 2024)
10-5200201-A-G			Benign (Jan 27, 2024)
10-5200206-T-C			Uncertain significance (Nov 28, 2022)
10-5200209-C-T		AKR1C4-related disorder	Uncertain significance (Mar 07, 2024)
10-5200223-G-A		AKR1C4-related disorder	Uncertain significance (Dec 26, 2023)
10-5200236-G-A			Uncertain significance (Oct 07, 2023)
10-5200261-CAAT-C		AKR1C4-related disorder	Likely benign (Dec 22, 2023)
10-5200268-G-A		AKR1C4-related disorder	Uncertain significance (Aug 29, 2023)
10-5200289-A-G		AKR1C4-related disorder	Uncertain significance (Jul 10, 2024)
10-5200312-C-T		AKR1C4-related disorder	Likely benign (Apr 04, 2022)
10-5200314-G-A		not specified	Uncertain significance (Mar 23, 2022)
10-5200323-G-C		AKR1C4-related disorder	Likely benign (Dec 04, 2023)
10-5200365-G-A			Likely benign (Jun 22, 2023)
10-5204395-C-G		not specified	Uncertain significance (Dec 28, 2022)
10-5204404-A-T		not specified	Likely benign (Sep 06, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AKR1C4	protein_coding	protein_coding	ENST00000380448	9	23488

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.23e-17	0.00108	125645	0	100	125745	0.000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.04	214	175	1.22	0.00000892	2108
Missense in Polyphen		84	73.641	1.1407		912
Synonymous	-0.951	73	63.4	1.15	0.00000309	601
Loss of Function	-0.916	23	18.7	1.23	9.74e-7	219

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000754	0.000754
Ashkenazi Jewish	0.000298	0.000198
East Asian	0.000545	0.000544
Finnish	0.00106	0.00106
European (Non-Finnish)	0.000337	0.000325
Middle Eastern	0.000545	0.000544
South Asian	0.000263	0.000261
Other	0.000497	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha- androstan-3-alpha,17-beta-diol (3-alpha-diol). Also has some 20- alpha-hydroxysteroid dehydrogenase activity. The biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leads to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route.
• Disease: DISEASE: 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:21802064}. Note=The gene represented in this entry may act as a disease modifier. A splicing mutation resulting in loss of AKR1C4 exon 2 has been found in affected individuals carrying a causative mutation in AKR1C2 (PubMed:21802064). These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2. {ECO:0000269|PubMed:21802064}.
• Pathway: Steroid hormone biosynthesis - Homo sapiens (human);Primary bile acid biosynthesis - Homo sapiens (human);27-Hydroxylase Deficiency;Bile Acid Biosynthesis;Steroidogenesis;Congenital Bile Acid Synthesis Defect Type II;Cerebrotendinous Xanthomatosis (CTX);Zellweger Syndrome;Familial Hypercholanemia (FHCA);Congenital Bile Acid Synthesis Defect Type III;Apparent mineralocorticoid excess syndrome;3-Beta-Hydroxysteroid Dehydrogenase Deficiency;21-hydroxylase deficiency (CYP21);Corticosterone methyl oxidase I deficiency (CMO I);Corticosterone methyl oxidase II deficiency - CMO II;Adrenal Hyperplasia Type 5 or Congenital Adrenal Hyperplasia due to 17 Alpha-hydroxylase Deficiency;Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia due to 21-hydroxylase Deficiency;Congenital Lipoid Adrenal Hyperplasia (CLAH) or Lipoid CAH;17-alpha-hydroxylase deficiency (CYP17);11-beta-hydroxylase deficiency (CYP11B1);Benzo(a)pyrene metabolism;Metapathway biotransformation Phase I and II;Signaling by GPCR;Signal Transduction;Metabolism of fat-soluble vitamins;Metabolism of lipids;Metabolism;Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol;allopregnanolone biosynthesis;Synthesis of bile acids and bile salts via 24-hydroxycholesterol;Synthesis of bile acids and bile salts via 27-hydroxycholesterol;Synthesis of bile acids and bile salts;Bile acid and bile salt metabolism;Metabolism of steroids;Metabolism of vitamins and cofactors;Retinoid metabolism and transport;G alpha (i) signalling events;Visual phototransduction;GPCR downstream signalling (Consensus)

Recessive Scores

• pRec: 0.154

Intolerance Scores

• loftool: 0.903
• rvis_EVS: 0
• rvis_percentile_EVS: 53.85

Haploinsufficiency Scores

• pHI: 0.180
• hipred: N
• hipred_score: 0.112
• ghis: 0.396

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.334

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Akr1c6

Gene ontology

• Biological process: retinoid metabolic process;prostaglandin metabolic process;bile acid biosynthetic process;steroid metabolic process;androgen metabolic process;bile acid and bile salt transport;electron transport chain;progesterone metabolic process;daunorubicin metabolic process;doxorubicin metabolic process;cellular response to jasmonic acid stimulus
• Cellular component: cytoplasm;cytosol;extracellular exosome
• Molecular function: retinal dehydrogenase activity;alditol:NADP+ 1-oxidoreductase activity;aldo-keto reductase (NADP) activity;alcohol dehydrogenase (NADP+) activity;electron transfer activity;bile acid transmembrane transporter activity;steroid dehydrogenase activity;oxidoreductase activity;oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor;androsterone dehydrogenase activity;ketosteroid monooxygenase activity;chlordecone reductase activity