CYB5A

protein-coding

cytochrome b5 type A

Gene summary

The protein encoded by this gene is a membrane-bound cytochrome that reduces ferric hemoglobin (methemoglobin) to ferrous hemoglobin, which is required for stearyl-CoA-desaturase activity. Defects in this gene are a cause of type IV hereditary methemoglobinemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

Previous symbols:

CYB5

MANE transcript

NM_148923.4

Inheritance

ClinVar variants

P:3U:16B:4

Top phenotype

Methemoglobinemia and ambiguous genitalia

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr18:74,250,846-74,291,973

External References & Databases

Ensembl (ENSG00000166347)

Transcript & Mutation Effects

hg38 • Region Span ~41.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methemoglobinemia type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009605

Submitter: Labcorp Genetics (formerly Invitae)

46,XY disorder of sex development due to isolated 17,20-lyase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019597

Submitter: Orphanet

methemoglobinemia type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009605

Submitter: ClinGen

*CYB5A* was first reported in relation to autosomal recessive methemoglobinemia 4 by Giordano et al. in 1994 (PMID: 8168836) in a family that had previously been reported in 1986 (Hegesh et al., PMID: 3951505). Methemoglobinemia 4, also referred to as methemoglobinemia and ambiguous genitalia (MIM#250790) or pure isolated 17,20-lyase deficiency, is characterized by mildly elevated serum methemoglobin, cyanosis, and 46,XY disorder of sexual differentiation (DSD). The cytochrome b5 protein encoded by *CYB5A* interacts with cytochrome P450 17A1 and stimulates 17,20-lyase activity, which is required for the synthesis of androgen hormones. Biallelic loss of *CYB5A* expression or disruption of this interaction leads to 46,XY DSD. To date, only one 46,XX proband with biallelic variants in *CYB5A* has been reported. This individual showed no evidence of DSD or other symptoms beyond elevated serum methemoglobin and cyanosis (PMID: 32051920). Six variants (missense, in-frame indel, nonsense, canonical splice acceptor site) that have been reported in five probands in five publications (PMIDs: 8168836, 20080843, 22170710, 32051920, 33626548) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, *in vitro* functional assays of wild-type function, and demonstrated protein-protein interactions with P450 17A1 (PMIDs: 20430864, 25613900, 26974035, 33753170, 34610701, 36441026). In summary, there is definitive evidence supporting the relationship between *CYB5A* and autosomal recessive methemoglobinemia 4. This association been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on November 8, 2024 (SOP Version 11).

Clinical Genomic Database (CGD)

Methemoglobinemia and ambiguous genitaliaAR

Manifestation: Endocrine; Hematologic; Oncologic; Genitourinary

Intervention: Endocrine; Oncologic; Genitourinary

Rationale: Hormonal treatment (eg, with estrogen or testosterone) may be beneficial related to sexual characteristics; Due to risk of gonadal tumors, surgical removal may be indicated

Refs: 3951505; 8168836; 22170710

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYB5A variants in ClinVar

4 Conditions Cataloged

not providedTotal: 9

not specifiedTotal: 9

CYB5A-related disorderTotal: 3

Methemoglobinemia type 4Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_148923.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	2 clinvar		4
missense		1 clinvar	9 clinvar	2 clinvar		12
nonsense		1 clinvar				1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		5 clinvar			6
Total	1	2	16	4	0	23

Highest pathogenic variant AF is 0.0000013681238

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_148923.4	RefSeq	NP_683725.1	5	MANE Select
ENST00000340533.9	Ensembl	ENSP00000341625.4	5	MANE Select
NM_001190807.3	RefSeq	NP_001177736.1	4	Standard
NM_001914.4	RefSeq	NP_001905.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Methylene Blue Pathway, Pharmacodynamics
Oxidation by Cytochrome P450
Vitamin C (ascorbate) metabolism
Metabolism
Metabolism of water-soluble vitamins and cofactors

Biological Process

L-ascorbic acid metabolic process
electron transport chain
response to cadmium ion
proton transmembrane transport

Molecular Function

aldo-keto reductase (NADP) activity
cytochrome-c oxidase activity
enzyme binding
heme binding
metal ion binding

Cellular Component

mitochondrial outer membrane
endoplasmic reticulum membrane
cytosol
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340533
Coding exons: 5
Length: 38722
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0855	76	73.9	1.03	0.00000381	892
Missense (PolyPhen)		24	20.914	1.1476		274
Synonymous	-1.60	37	26.5	1.40	0.00000146	236
Loss of Function	0.784	5	7.28	0.687	3.11e-7	90

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytochrome b5 is a membrane bound hemoprotein which function as an electron carrier for several membrane bound oxygenases.;
Disease: DISEASE: Methemoglobinemia and ambiguous genitalia (METAG) [MIM:250790]: An autosomal recessive disorder characterized by sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve, male undermasculinization, absent or disturbed pubertal development, decreased levels of erythrocyte cytochrome B5, and excessive amounts of methemoglobin in blood cells resulting in cyanosis and hypoxia. {ECO:0000269|PubMed:20080843, ECO:0000269|PubMed:22170710, ECO:0000269|PubMed:8168836}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.335

Intolerance Scores

LoFtool: 0.354
RVIS EVS: 0.08
RVIS percentile EVS: 59.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.854

Gene Damage Prediction

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