GeneBe

CYB5R3

cytochrome b5 reductase 3

Basic information

Region (hg38): 22:42615730-42720870

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

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Methemoglobinemia due to methemoglobin reductase deficiencyARBiochemical; PharmacogenomicSome 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 reactionsBiochemical; Hematologic; Neurologic21011935; 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 (145 variants)
  • Deficiency_of_cytochrome-b5_reductase (54 variants)
  • Inborn_genetic_diseases (39 variants)
  • not_specified (24 variants)
  • METHEMOGLOBINEMIA,_TYPE_I (12 variants)
  • CYB5R3-related_disorder (11 variants)
  • METHEMOGLOBINEMIA,_TYPE_II (10 variants)
  • Central_core_myopathy (4 variants)
  • Hereditary_methemoglobinemia (3 variants)
  • Neurodevelopmental_delay (1 variants)
  • Intellectual_disability (1 variants)
  • CYB5R3_POLYMORPHISM (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. These statistics are base on transcript: NM_000000398.7. 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.

EffectPLPVUSLBBSum
synonymous
28
clinvar
3
clinvar
 31
missense
7
clinvar
13
clinvar
96
clinvar
5
clinvar
2
clinvar
 123
nonsense
7
clinvar
 7
start loss
2
 2
frameshift
1
clinvar
1
clinvar
1
clinvar
 3
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
 4
Total 17 16 99 33 5

Highest pathogenic variant AF is 0.000120832

Loading clinvar variants...

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
CYB5R3protein_codingprotein_codingENST00000361740 931729
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.0001920.9781257150331257480.000131
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.4192222051.080.00001362176
Missense in Polyphen8078.1191.0241862
Synonymous0.1198081.40.9830.00000547639
Loss of Function2.03918.40.4890.00000104188

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0001850.000185
Ashkenazi Jewish0.000.00
East Asian0.0003260.000326
Finnish0.0005080.000508
European (Non-Finnish)0.00008800.0000879
Middle Eastern0.0003260.000326
South Asian0.00009800.0000980
Other0.000.00

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Cyb5r3
Phenotype

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