TYR
protein-codingtyrosinase
Gene summary
The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~117.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0018135
Submitter: ClinGen
The relationship between TYR and oculocutaneous albinism type 1 (OCA1) was evaluated using the ClinGen Clinical Validity Framework as of August 14, 2020. Oculocutaneous albinism (OCA) is an autosomal recessive disorder of melanin synthesis associated with a reduction of melanin pigment in the skin, hair, and eyes. Reduction of melanin in the eyes is associated with foveal hypoplasia and decreased visual acuity, misrouting of the optic nerve fibres from the retina to the visual cortex, nystagmus, strabismus and iris translucency (Oetting et al, 2003, PMID 12753405; Lewis, 2013, PMID 20301345). Notably, several genes have been implicated in OCA, and syndromic and non-syndromic forms of albinism have been described (Federico and Krishnamurthy, 2020, PMID 30085560). TYR, which has been implicated in OCA1, encodes tyrosinase, a copper-containing monooxygenase with a key role melanin synthesis. Melanin is made, stored and transported in pigment granules (melanosomes) in mammalian skin melanocytes, choroidal melanocytes and retinal pigment epithelial (RPE) cells in the eye (Wasmeier et al, 2008, PMID 19056669). Two types of OCA1 are described in the literature. OCA1A (historically known as “tyrosinase-negative OCA”), is the most severe form of the disorder. Tyrosinase activity is completely absent, and melanin pigment cannot be detected in the skin, hair or eyes of individuals with OCA1. There is low tyrosinase activity in individuals with OCA1B but some residual activity is present allowing some melanin to be produced, albeit at a reduced amount. Biallelic variants in TYR were first reported in 1989 (Tomita et al, PMID 2511845). Since then, more than 300 variants have been reported in TYR (PMID 30868138). Data from 9 probands who are homozygous or compound heterozygous for TYR variants were curated, including 12 unique variants (missense, nonsense, frameshift, splice site) (Tomita et al, 1989, PMID 2511845; Monfermé et al, 2019, PMID 30472657; Shakil et al, 2019, PMID 30996339; Lin et al, 2019, PMID 31199599; Schidlowski et al, 2020, PMID 32411182). This gene-disease relationship is supported by the biochemical role of TYR in the synthesis of melanin, which is consistent with the lack of pigmentation observed in individuals with OCA1 (Raper, 1926, PMID 16743714; Lai etal, 2018, PMID 29052256), functional alteration studies (Spritz et al, 1997, PMID 9242509; Totofuku et al, 2001, PMID 11284711), numerous natural and laboratory animal models including a spontaneous variant in mice (Le Fur et al, 1996, PMID 8921397), CRISPR-generated albino mice (Mizuno et al, 2014, OMID 24879364), and rescue of the phenotype by expression of tyrosinase in transgenic albino mice and medaka fish (Jeffery et al, 1994, PMID 7813769; Fu et al, 2000, PMID 10675031). In summary, TYR is definitively associated with OCA1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.
Inheritance Pattern: AR
Disease ID:MONDO:0008745
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019517
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008745
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008745
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0018137
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018136
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008745
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011749
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008745
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011749
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Variants may also be related to pigmentary manifestations such as skin, eye, and hair color, and related risk of skin cancer
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TYR variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000372.5. 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 | 5 | 165 | 1 | 171 | ||
| missense | 35 | 187 | 242 | 8 | 472 | |
| nonsense | 37 | 23 | 3 | 63 | ||
| start loss | 2 | 2 | ||||
| frameshift | 41 | 32 | 6 | 79 | ||
| splice donor/acceptor (+/-2bp) | 7 | 7 | 14 | |||
| Total | 120 | 251 | 256 | 173 | 1 | 801 |
Highest pathogenic variant AF is 0.004543678
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000363.1 | 5 | MANE Select | |
| Ensembl | ENSP00000263321.4 | 5 | MANE Select | |
| RefSeq | XP_011541272.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tyr | Danio rerio | Structure: melanoblast Quality: unpigmented abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Tyrosine metabolism - Homo sapiens (human)
- Melanogenesis - Homo sapiens (human)
- Tyrosinemia, transient, of the newborn
- Dopamine beta-hydroxylase deficiency
- Disulfiram Action Pathway
Biological Process
- melanin biosynthetic process from tyrosine
- eye pigment biosynthetic process
- visual perception
- cell population proliferation
- response to UV
Molecular Function
- monooxygenase activity
- monophenol monooxygenase activity
- copper ion binding
- protein binding
- protein homodimerization activity
Cellular Component
- nucleus
- cytoplasm
- lysosome
- Golgi-associated vesicle
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000263321
- Coding exons
- 5
- Length
- 118308
- Individuals with no LoFs
- 125574
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 174
- Defined
- 125748
- p
- 0.000692
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.95 | 379 | 286 | 1.32 | 0.0000155 | 3499 |
| Missense (PolyPhen) | 156 | 113.59 | 1.3734 | 1442 | ||
| Synonymous | -2.41 | 139 | 107 | 1.30 | 0.00000601 | 990 |
| Loss of Function | -3.29 | 38 | 21.5 | 1.77 | 0.00000120 | 244 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00062 | 0.00062 | rare |
| Latino/Admixed American | 0.00058 | 0.00058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00098 | 0.00098 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00068 | 0.00060 | rare |
| South Asian | 0.0017 | 0.0017 | notable |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyzes the initial and rate limiting step in the cascade of reactions leading to melanin production from tyrosine. In addition to hydroxylating tyrosine to DOPA (3,4- dihydroxyphenylalanine), also catalyzes the oxidation of DOPA to DOPA-quinone, and possibly the oxidation of DHI (5,6- dihydroxyindole) to indole-5,6 quinone. {ECO:0000250|UniProtKB:P11344}.;
- Disease
- DISEASE: Albinism, oculocutaneous, 1A (OCA1A) [MIM:203100]: An autosomal recessive disorder in which the biosynthesis of melanin pigment is absent in skin, hair, and eyes. It is characterized by complete lack of tyrosinase activity due to production of an inactive enzyme. Patients present with a life-long absence of melanin pigment after birth, and manifest increased sensitivity to ultraviolet radiation with predisposition to skin cancer. Visual anomalies include decreased acuity, nystagmus, strabismus and photophobia. {ECO:0000269|PubMed:10571953, ECO:0000269|PubMed:10671066, ECO:0000269|PubMed:10987646, ECO:0000269|PubMed:11295837, ECO:0000269|PubMed:11858948, ECO:0000269|PubMed:1487241, ECO:0000269|PubMed:15146472, ECO:0000269|PubMed:1642278, ECO:0000269|PubMed:1899321, ECO:0000269|PubMed:1943686, ECO:0000269|PubMed:1970634, ECO:0000269|PubMed:22981120, ECO:0000269|PubMed:2342539, ECO:0000269|PubMed:23504663, ECO:0000269|PubMed:24934919, ECO:0000269|PubMed:7902671, ECO:0000269|PubMed:7955413, ECO:0000269|PubMed:8128955, ECO:0000269|PubMed:8644824, ECO:0000269|PubMed:9259202}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Albinism, oculocutaneous, 1B (OCA1B) [MIM:606952]: An autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. It is characterized by partial lack of tyrosinase activity. Patients have white hair at birth that rapidly turns yellow or blond. They manifest the development of minimal-to-moderate amounts of cutaneous and ocular pigment. Some patients may have with white hair in the warmer areas (scalp and axilla) and progressively darker hair in the cooler areas (extremities). This variant phenotype is due to a loss of tyrosinase activity above 35-37 degrees C. {ECO:0000269|PubMed:10987646, ECO:0000269|PubMed:1900309, ECO:0000269|PubMed:1903591, ECO:0000269|PubMed:8128955}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.893
Intolerance Scores
- LoFtool
- 0.0937
- RVIS EVS
- -0.95
- RVIS percentile EVS
- 9.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.781
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |