LATS1

protein-coding

large tumor suppressor kinase 1, the group of AGC family kinases

Gene summary

The protein encoded by this gene is a putative serine/threonine kinase that localizes to the mitotic apparatus and complexes with cell cycle controller CDC2 kinase in early mitosis. The protein is phosphorylated in a cell-cycle dependent manner, with late prophase phosphorylation remaining through metaphase. The N-terminal region of the protein binds CDC2 to form a complex showing reduced H1 histone kinase activity, indicating a role as a negative regulator of CDC2/cyclin A. In addition, the C-terminal kinase domain binds to its own N-terminal region, suggesting potential negative regulation through interference with complex formation via intramolecular binding. Biochemical and genetic data suggest a role as a tumor suppressor. This is supported by studies in knockout mice showing development of soft-tissue sarcomas, ovarian stromal cell tumors and a high sensitivity to carcinogenic treatments. [provided by RefSeq, Apr 2017]

MANE transcript

NM_004690.4

Inheritance

—

ClinVar variants

P:3U:111B:5

Top phenotype

Multiple myeloma

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr6:149,658,153-149,718,105

External References & Databases

Ensembl (ENSG00000131023)

Transcript & Mutation Effects

hg38 • Region Span ~60.0 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 LATS1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 99

not providedTotal: 6

Multiple myelomaTotal: 1

TeratomaTotal: 1

Myoepithelial tumorTotal: 1

Malignant peritoneal mesotheliomaTotal: 1

EpendymomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004690.4. 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			4 clinvar	1 clinvar		5
missense	1 clinvar	1 clinvar	103 clinvar	3 clinvar	1 clinvar	109
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	1	2	111	4	1	119

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004690.4	RefSeq	NP_004681.1	7	MANE Select
ENST00000543571.6	Ensembl	ENSP00000437550.1	7	MANE Select
NM_001270519.2	RefSeq	NP_001257448.1	3	Standard
NM_001350339.2	RefSeq	NP_001337268.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lats1	Danio rerio	Structure: convergent extension involved in gastrulation Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

lats1

Danio rerio

Structure: convergent extension involved in gastrulation

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hippo signaling pathway - Homo sapiens (human)
Hippo signaling pathway - multiple species - Homo sapiens (human)
Mesodermal Commitment Pathway
Signal Transduction
Signaling by Hippo

Biological Process

G1/S transition of mitotic cell cycle
G2/M transition of mitotic cell cycle
sister chromatid segregation
inner cell mass cell fate commitment
inner cell mass cellular morphogenesis

Molecular Function

magnesium ion binding
protein serine/threonine kinase activity
protein binding
ATP binding
protein kinase binding

Cellular Component

spindle pole
microtubule organizing center
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000543571
Coding exons: 7
Length: 60104
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125747
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.31	454	615	0.738	0.0000321	7466
Missense (PolyPhen)		144	264.14	0.54517		3095
Synonymous	0.104	202	204	0.991	0.0000103	2182
Loss of Function	5.90	6	51.9	0.116	0.00000335	524

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negative regulator of YAP1 in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Acts as a tumor suppressor which plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint. Negatively regulates G2/M transition by down-regulating CDK1 kinase activity. Involved in the control of p53 expression. Affects cytokinesis by regulating actin polymerization through negative modulation of LIMK1. May also play a role in endocrine function. Plays a role in mammary gland epithelial cells differentiation, both through the Hippo signaling pathway and the intracellular estrogen receptor signaling pathway by promoting the degradation of ESR1 (PubMed:28068668). {ECO:0000269|PubMed:10518011, ECO:0000269|PubMed:10831611, ECO:0000269|PubMed:15122335, ECO:0000269|PubMed:15220930, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:19927127, ECO:0000269|PubMed:28068668}.;

Recessive Scores

pRec: 0.585

Intolerance Scores

LoFtool: 0.250
RVIS EVS: -0.02
RVIS percentile EVS: 52.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.954

Gene Damage Prediction

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