TLK1

protein-coding

tousled like kinase 1

Gene summary

The protein encoded by this gene is a serine/threonine kinase that may be involved in the regulation of chromatin assembly. The encoded protein is only active when it is phosphorylated, and this phosphorylation is cell cycle-dependent, with the maximal activity of this protein coming during S phase. The catalytic activity of this protein is diminished by DNA damage and by blockage of DNA replication. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

MANE transcript

NM_012290.5

Inheritance

—

ClinVar variants

U:57B:1

Top phenotype

Neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr2:170,990,823-171,231,314

External References & Databases

Ensembl (ENSG00000198586)

Transcript & Mutation Effects

hg38 • Region Span ~240.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLK1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 44

not providedTotal: 3

Neurodevelopmental disorderTotal: 1

See casesTotal: 1

TLK1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012290.5. 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			2 clinvar	1 clinvar		3
missense			47 clinvar			47
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	57	1	0	58

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012290.5	RefSeq	NP_036422.3	21	MANE Select
ENST00000431350.7	Ensembl	ENSP00000411099.2	21	MANE Select
NM_001136554.2	RefSeq	NP_001130026.1	20	Standard
NM_001136555.2	RefSeq	NP_001130027.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miRNA Regulation of DNA Damage Response
Pathways Affected in Adenoid Cystic Carcinoma
DNA Damage Response

Biological Process

regulation of chromatin assembly or disassembly
chromatin organization
protein phosphorylation
intracellular protein transport
cellular response to DNA damage stimulus

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000431350
Coding exons: 21
Length: 240492
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.56	200	401	0.499	0.0000202	5034
Missense (PolyPhen)		47	158.8	0.29598		2030
Synonymous	0.439	133	140	0.953	0.00000691	1386
Loss of Function	5.95	3	47.0	0.0638	0.00000244	587

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	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000070	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S- phase. This is cell cycle checkpoint and ATM-pathway dependent and appears to regulate processes involved in chromatin assembly. Isoform 3 phosphorylates and enhances the stability of the t-SNARE SNAP23, augmenting its assembly with syntaxin. Isoform 3 protects the cells from the ionizing radiation by facilitating the repair of DSBs. In vitro, phosphorylates histone H3 at 'Ser-10'. {ECO:0000269|PubMed:10523312, ECO:0000269|PubMed:10588641, ECO:0000269|PubMed:11314006, ECO:0000269|PubMed:11470414, ECO:0000269|PubMed:12660173, ECO:0000269|PubMed:9427565}.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.0789
RVIS EVS: -0.4
RVIS percentile EVS: 26.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.827

Gene Damage Prediction

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