PTTG1

protein-coding

PTTG1 regulator of sister chromatid separation, securin

Gene summary

The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

Previous symbols:

TUTR1

MANE transcript

NM_004219.4

Inheritance

—

ClinVar variants

U:24B:2

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr5:160,421,855-160,428,739

External References & Databases

Ensembl (ENSG00000164611)

Transcript & Mutation Effects

hg38 • Region Span ~6.9 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 PTTG1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 22

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004219.4. 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					1 clinvar	1
missense			23 clinvar	1 clinvar		24
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	24	1	1	26

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004219.4	RefSeq	NP_004210.1	5	MANE Select
ENST00000352433.10	Ensembl	ENSP00000344936.5	5	MANE Select
NM_001282382.1	RefSeq	NP_001269311.1	5	Standard
NM_001282383.1	RefSeq	NP_001269312.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Cell Cycle
Regulation of sister chromatid separation at the metaphase-anaphase transition

Biological Process

DNA repair
regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
spermatogenesis
negative regulation of endopeptidase activity

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
cysteine-type endopeptidase inhibitor activity
protein binding
SH3 domain binding

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393964
Coding exons: 5
Length: 6920
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.961	78	106	0.737	0.00000503	1300
Missense (PolyPhen)		11	27.791	0.39582		387
Synonymous	-0.0264	41	40.8	1.01	0.00000214	409
Loss of Function	0.748	6	8.33	0.720	3.48e-7	118

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulatory protein, which plays a central role in chromosome stability, in the p53/TP53 pathway, and DNA repair. Probably acts by blocking the action of key proteins. During the mitosis, it blocks Separase/ESPL1 function, preventing the proteolysis of the cohesin complex and the subsequent segregation of the chromosomes. At the onset of anaphase, it is ubiquitinated, conducting to its destruction and to the liberation of ESPL1. Its function is however not limited to a blocking activity, since it is required to activate ESPL1. Negatively regulates the transcriptional activity and related apoptosis activity of TP53. The negative regulation of TP53 may explain the strong transforming capability of the protein when it is overexpressed. May also play a role in DNA repair via its interaction with Ku, possibly by connecting DNA damage-response pathways with sister chromatid separation. {ECO:0000269|PubMed:10411507, ECO:0000269|PubMed:11238996, ECO:0000269|PubMed:11371342, ECO:0000269|PubMed:12355087}.;

Recessive Scores

pRec: 0.317

Intolerance Scores

LoFtool: 0.533
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.968

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low