CYB5R3

cytochrome b5 reductase 3

Basic information

Region (hg38): 22:42615729-42720870

Previous symbols: [ "DIA1" ]

Links

ENSG00000100243 ∙ NCBI:1727 ∙ OMIM:613213 ∙ HGNC:2873 ∙ Uniprot:P00387 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methemoglobinemia due to deficiency of methemoglobin reductase (Strong), mode of inheritance: AR
• hereditary methemoglobinemia (Supportive), mode of inheritance: AR
• methemoglobinemia (Definitive), mode of inheritance: AR
• methemoglobinemia due to deficiency of methemoglobin reductase (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methemoglobinemia due to methemoglobin reductase deficiency	AR	Biochemical; Pharmacogenomic	Some forms of disease are responsive to medical therapy (eg, with ascorbic acid), though neurological manifestations in severe forms have not been described as being impacted by this type of management; In treatment with certain medications (eg, Dapsone), genotyping may assist in the prevention and/or early treatment of adverse reactions	Biochemical; Hematologic; Neurologic	21011935; 18861684; 1207738; 4063522; 3539237; 1707593; 8427971; 7668255; 7718898; 9266404; 9695975; 10874300; 12803131; 15921385; 15390276; 17964195; 18202104; 18343696; 18820099; 18318771; 19579085; 19997042; 21328435; 22627575; 22658170; 22797852

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CYB5R3 gene.

• not provided (174 variants)
• Inborn genetic diseases (36 variants)
• Deficiency of cytochrome-b5 reductase (31 variants)
• not specified (7 variants)
• Methemoglobinemia, type I (5 variants)
• CYB5R3-related condition (3 variants)
• Methemoglobinemia type 2 (2 variants)
• Hereditary methemoglobinemia (1 variants)
• NADH-CYTOCHROME b5 REDUCTASE POLYMORPHISM (1 variants)
• p phenotype (1 variants)
• Neurodevelopmental delay (1 variants)
• Infantile cortical hyperostosis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CYB5R3 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				19	4	23
missense		5	46	2	1	54
nonsense	4					4
start loss			1			1
frameshift	1		1			2
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	2				3
splice region			1	6	1	8
non coding			44	26	48	118
Total	6	7	93	47	53

Highest pathogenic variant AF is 0.0000329

Variants in CYB5R3

This is a list of pathogenic ClinVar variants found in the CYB5R3 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-42619486-G-T			Benign (Nov 12, 2018)
22-42619710-T-C			Benign (Nov 12, 2018)
22-42619773-T-C		Hereditary methemoglobinemia	Uncertain significance (-)
22-42619776-G-A			Likely benign (Mar 01, 2023)
22-42619781-C-T			Benign/Likely benign (Jan 15, 2024)
22-42619781-CGAA-C		Methemoglobinemia type 2	Pathogenic (May 01, 2008)
22-42619789-C-T		Neurodevelopmental delay • CYB5R3-related disorder	Conflicting classifications of pathogenicity (Jan 15, 2024)
22-42619795-G-A			Uncertain significance (Mar 24, 2020)
22-42619799-GGTGGCCCAC-G			Uncertain significance (Oct 29, 2020)
22-42619804-C-T		Methemoglobinemia, type I • Deficiency of cytochrome-b5 reductase	Pathogenic/Likely pathogenic (Aug 15, 2023)
22-42619808-C-T			Uncertain significance (Nov 25, 2019)
22-42619809-G-A		CYB5R3-related disorder	Likely benign (Jan 12, 2023)
22-42619817-G-C		Inborn genetic diseases	Uncertain significance (Oct 06, 2023)
22-42619818-G-C			Uncertain significance (May 04, 2023)
22-42619833-G-A			Benign (Oct 17, 2023)
22-42619848-T-TG		Deficiency of cytochrome-b5 reductase	Pathogenic (Jun 23, 2021)
22-42619849-G-A			Uncertain significance (May 19, 2022)
22-42619859-ACAT-A		Methemoglobinemia type 2	Pathogenic (May 01, 2008)
22-42619872-C-T			Likely benign (Nov 28, 2023)
22-42619873-G-A		Deficiency of cytochrome-b5 reductase	Conflicting classifications of pathogenicity (Aug 09, 2022)
22-42619874-G-T			Uncertain significance (Jun 20, 2023)
22-42619883-C-G		Deficiency of cytochrome-b5 reductase	Uncertain significance (Sep 17, 2022)
22-42619903-C-T			Uncertain significance (Aug 22, 2022)
22-42619904-G-A			Uncertain significance (Jan 19, 2024)
22-42619910-TCTC-T		Methemoglobinemia, type I	Pathogenic (May 01, 2008)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CYB5R3	protein_coding	protein_coding	ENST00000361740	9	31729

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000192	0.978	125715	0	33	125748	0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.419	222	205	1.08	0.0000136	2176
Missense in Polyphen		80	78.119	1.0241		862
Synonymous	0.119	80	81.4	0.983	0.00000547	639
Loss of Function	2.03	9	18.4	0.489	0.00000104	188

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000185	0.000185
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.000508	0.000508
European (Non-Finnish)	0.0000880	0.0000879
Middle Eastern	0.000326	0.000326
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.
• Disease: DISEASE: Methemoglobinemia CYB5R3-related (METHB-CYB5R3) [MIM:250800]: A form of methemoglobinemia, a hematologic disease characterized by the presence of excessive amounts of methemoglobin in blood cells, resulting in decreased oxygen carrying capacity of the blood, cyanosis and hypoxia. There are two types of methemoglobinemia CYB5R3-related. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms. {ECO:0000269|PubMed:10807796, ECO:0000269|PubMed:12393396, ECO:0000269|PubMed:1400360, ECO:0000269|PubMed:15622768, ECO:0000269|PubMed:15953014, ECO:0000269|PubMed:1707593, ECO:0000269|PubMed:1898726, ECO:0000269|PubMed:7718898, ECO:0000269|PubMed:8119939, ECO:0000269|PubMed:9695975, ECO:0000269|PubMed:9886302}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Amino sugar and nucleotide sugar metabolism - Homo sapiens (human);Methylene Blue Pathway, Pharmacodynamics;Oxidation by Cytochrome P450;Neutrophil degranulation;Phase I - Functionalization of compounds;Vitamin C (ascorbate) metabolism;Biological oxidations;Vitamin B3 (nicotinate and nicotinamide) metabolism;Innate Immune System;Immune System;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.282

Intolerance Scores

• loftool: 0.0159
• rvis_EVS: 0.51
• rvis_percentile_EVS: 80.2

Haploinsufficiency Scores

• pHI: 0.206
• hipred: N
• hipred_score: 0.499
• ghis: 0.564

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.532

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cyb5r3

Gene ontology

• Biological process: cholesterol biosynthetic process;blood circulation;L-ascorbic acid metabolic process;neutrophil degranulation;oxidation-reduction process
• Cellular component: extracellular region;cytoplasm;mitochondrion;mitochondrial outer membrane;endoplasmic reticulum;endoplasmic reticulum membrane;lipid droplet;hemoglobin complex;membrane;azurophil granule lumen
• Molecular function: cytochrome-b5 reductase activity, acting on NAD(P)H;protein binding;AMP binding;ADP binding;NAD binding;FAD binding