TTL

protein-coding

tubulin tyrosine ligase, the group of Tubulin tyrosine ligase family

Gene summary

TTL is a cytosolic enzyme involved in the posttranslational modification of alpha-tubulin (see MIM 602529). Alpha-tubulin within assembled microtubules is detyrosinated over time at the C terminus. After microtubule disassembly, TTL restores the tyrosine residues and consequently participates in a cycle of tubulin detyrosination and tyrosination (Erck et al., 2003 [PubMed 14571137]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_153712.5

Inheritance

AD, AR

ClinVar variants

U:39B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr2:112,482,156-112,541,739

External References & Databases

Ensembl (ENSG00000114999)

Transcript & Mutation Effects

hg38 • Region Span ~59.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypertrophic cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTL variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 33

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153712.5. 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			1 clinvar		1 clinvar	2
missense			35 clinvar	1 clinvar	1 clinvar	37
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	39	1	2	42

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153712.5	RefSeq	NP_714923.1	7	MANE Select
ENST00000233336.7	Ensembl	ENSP00000233336.5	7	MANE Select
NM_001371712.1	RefSeq	NP_001358641.1	7	Standard
ENST00000901134.1	Ensembl	ENSP00000571193.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Carboxyterminal post-translational modifications of tubulin

Biological Process

microtubule cytoskeleton organization
C-terminal protein-tyrosinylation
regulation of axon extension
positive regulation of mitotic cell cycle
regulation of metaphase plate congression

Molecular Function

tubulin-tyrosine ligase activity
ATP binding

Cellular Component

cell

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000233336
Coding exons: 7
Length: 59586
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.71	135	204	0.663	0.0000100	2466
Missense (PolyPhen)		31	79.208	0.39137		912
Synonymous	-0.222	84	81.4	1.03	0.00000447	710
Loss of Function	3.01	4	17.6	0.227	7.92e-7	222

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)	0.000090	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the post-translational addition of a tyrosine to the C-terminal end of detyrosinated alpha-tubulin. {ECO:0000269|PubMed:25908662}.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.0843
RVIS EVS: -0.07
RVIS percentile EVS: 48.35

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.234

Gene Damage Prediction

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