TAT

protein-coding

tyrosine aminotransferase

Gene summary

This nuclear gene encodes a mitochondrial protein tyrosine aminotransferase which is present in the liver and catalyzes the conversion of L-tyrosine into p-hydroxyphenylpyruvate. Mutations in this gene cause tyrosinemia (type II, Richner-Hanhart syndrome), a disorder accompanied by major skin and corneal lesions, with possible cognitive disability. A regulator gene for tyrosine aminotransferase is X-linked. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000353.3

Inheritance

ClinVar variants

P:71U:67B:177

Top phenotype

Tyrosinemia, type II

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr16:71,565,660-71,577,092

External References & Databases

Ensembl (ENSG00000198650)

Transcript & Mutation Effects

hg38 • Region Span ~11.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tyrosinemia type IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: Genomics England PanelApp

tyrosinemia type IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: ClinGen

TAT was first reported in relation to autosomal recessive Tyrosinemia Type II in 1992 (Natt et al., 1992 PMID 1357662). At least 22 unique variants (including many missense/nonsense, as well as frameshift and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 points Variants in this gene have been reported in at least 10 probands in 6 publications (PMIDs: 9544843, 16917729, 1357662, 16318910, 27832414, 18945316). Variants in this gene segregated with disease in 8 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Summary of Experimental Evidence: 0.5 points This gene-disease relationship is supported by the biochemical function of TAT, the conversion of tyrosine to p-hydroxylphenylpyruvate. Hypertyrosinemia occurs due to lack of TAT enzymatic activity. In summary, TAT is definitively associated with autosomal recessive Tyrosinemia Type II. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

tyrosinemia type IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: Labcorp Genetics (formerly Invitae)

tyrosinemia type IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: Myriad Women's Health

tyrosinemia type IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: PanelApp Australia

tyrosinemia type IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: G2P

tyrosinemia type IISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010160

Submitter: Orphanet

Clinical Genomic Database (CGD)

Tyrosinemia, type IIAR

Manifestation: Biochemical; Dermatologic; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Dietary measures (controlled intake of phenylalanine and tyrosine) can be effective, including as relates to neurocognitive outcome

Refs: 18901242; 33934; 6446465; 1356171; 1357662; 8912606; 12227462; 9544843; 16574453; 16917729; 18945316; 21145993; 21636300

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TAT variants in ClinVar

6 Conditions Cataloged

Tyrosinemia type IITotal: 412

Inborn genetic diseasesTotal: 23

not providedTotal: 13

not specifiedTotal: 11

TAT-related disorderTotal: 4

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000353.3. 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		1 clinvar	2 clinvar	172 clinvar	2 clinvar	177
missense	2 clinvar	9 clinvar	63 clinvar	2 clinvar	1 clinvar	77
nonsense	7 clinvar	8 clinvar				15
start loss		1 clinvar				1
frameshift	9 clinvar	16 clinvar				25
splice donor/acceptor (+/-2bp)	1 clinvar	17 clinvar	2 clinvar			20
Total	19	52	67	174	3	315

Highest pathogenic variant AF is 0.000039650826

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000353.3	RefSeq	NP_000344.1	11	MANE Select
ENST00000355962.5	Ensembl	ENSP00000348234.4	11	MANE Select
ENST00000895691.1	Ensembl	ENSP00000565750.1	10	Standard
ENST00000895691.2	Ensembl	ENSP00000565750.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquinone and other terpenoid-quinone biosynthesis - Homo sapiens (human)
Phenylalanine metabolism - Homo sapiens (human)
Phenylalanine, tyrosine and tryptophan biosynthesis - Homo sapiens (human)
Cysteine and methionine metabolism - Homo sapiens (human)
Tyrosine metabolism - Homo sapiens (human)

Biological Process

2-oxoglutarate metabolic process
glutamate metabolic process
L-phenylalanine catabolic process
tyrosine catabolic process
response to oxidative stress

Molecular Function

L-tyrosine:2-oxoglutarate aminotransferase activity
protein binding
amino acid binding
pyridoxal phosphate binding

Cellular Component

cellular_component
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355962
Coding exons: 11
Length: 11471
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.760	220	254	0.866	0.0000147	2969
Missense (PolyPhen)		57	83.654	0.68138		996
Synonymous	0.384	89	93.7	0.950	0.00000527	884
Loss of Function	2.97	8	23.5	0.340	0.00000139	275

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transaminase involved in tyrosine breakdown. Converts tyrosine to p-hydroxyphenylpyruvate. Can catalyze the reverse reaction, using glutamic acid, with 2-oxoglutarate as cosubstrate (in vitro). Has much lower affinity and transaminase activity towards phenylalanine. {ECO:0000269|PubMed:16640556, ECO:0000269|PubMed:7999802}.;
Disease: DISEASE: Tyrosinemia 2 (TYRSN2) [MIM:276600]: An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, and oculocutaneous manifestations. Typical features include palmoplantar keratosis, painful corneal ulcers, and mental retardation. {ECO:0000269|PubMed:1357662}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.709

Intolerance Scores

LoFtool: 0.244
RVIS EVS: -0.56
RVIS percentile EVS: 19.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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