CYP19A1
protein-codingcytochrome P450 family 19 subfamily A member 1, the group of Cytochrome P450 family 19|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and catalyzes the last steps of estrogen biosynthesis. Mutations in this gene can result in either increased or decreased aromatase activity; the associated phenotypes suggest that estrogen functions both as a sex steroid hormone and in growth or differentiation. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]
- CYP19
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~130.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013301
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007690
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013301
Submitter: Natera
Inheritance Pattern: AD
Disease ID:MONDO:0007690
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013301
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013301
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007690
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: Endocrine
Rationale: In Aromatase excess syndrome, medical treatment (eg, with aromatase inhibitors) can be beneficial; In Androgen deficiency, females may present with virilization resulting in manifestations such as pseudohermaphroditism, while males may present later with manifestations such as delayed skeletal maturation and epiphyseal closure, skeletal pain, eunuchoid habitus and increased adiposity, and estrogen therapy reverses symptoms
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CYP19A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000103.4. 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 | 8 | 197 | 5 | 210 | ||
| missense | 1 | 14 | 84 | 7 | 1 | 107 |
| nonsense | 12 | 12 | 24 | |||
| start loss | 0 | |||||
| frameshift | 24 | 7 | 31 | |||
| splice donor/acceptor (+/-2bp) | 4 | 12 | 1 | 17 | ||
| Total | 41 | 45 | 93 | 204 | 6 | 389 |
Highest pathogenic variant AF is 0.000039637747
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000094.2 | 9 | MANE Select | |
| Ensembl | ENSP00000379683.1 | 9 | MANE Select | |
| RefSeq | NP_001334177.1 | 9 | Standard | |
| RefSeq | NP_001334178.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cyp19a1a | Danio rerio | Structure: germ line cell Quality: increased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Steroid hormone biosynthesis - Homo sapiens (human)
- Ovarian steroidogenesis - Homo sapiens (human)
- Aromatase Inhibitor Pathway (Multiple Tissues), Pharmacodynamics
- Estrogen Metabolism Pathway
- Aromatase Inhibitor Pathway (Breast Cell), Pharmacodynamics
Biological Process
- negative regulation of chronic inflammatory response
- steroid biosynthetic process
- estrogen biosynthetic process
- androgen catabolic process
- female gonad development
Molecular Function
- iron ion binding
- steroid hydroxylase activity
- electron transfer activity
- oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- oxygen binding
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396402
- Coding exons
- 9
- Length
- 130554
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125748
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.535 | 263 | 289 | 0.911 | 0.0000160 | 3360 |
| Missense (PolyPhen) | 99 | 122.42 | 0.80872 | 1454 | ||
| Synonymous | -0.654 | 109 | 101 | 1.08 | 0.00000581 | 928 |
| Loss of Function | 1.99 | 11 | 20.8 | 0.530 | 0.00000110 | 258 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the formation of aromatic C18 estrogens from C19 androgens.;
- Disease
- DISEASE: Aromatase excess syndrome (AEXS) [MIM:139300]: An autosomal dominant disorder characterized by increased extraglandular aromatization of steroids that presents with heterosexual precocity in males and isosexual precocity in females. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Aromatase deficiency (AROD) [MIM:613546]: A rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries. {ECO:0000269|PubMed:24705274, ECO:0000269|PubMed:8265607, ECO:0000269|PubMed:8530621, ECO:0000269|PubMed:9211678}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.854
Intolerance Scores
- LoFtool
- 0.495
- RVIS EVS
- -0.56
- RVIS percentile EVS
- 19.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.767
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |