POT1

protection of telomeres 1, the group of Shelterin complex

Basic information

Region (hg38): 7:124822385-124929983

Links

ENSG00000128513 ∙ NCBI:25913 ∙ OMIM:606478 ∙ HGNC:17284 ∙ Uniprot:Q9NUX5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• glioma susceptibility 9 (Limited), mode of inheritance: AD
• tumor predisposition syndrome 3 (Moderate), mode of inheritance: AD
• pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8 (Strong), mode of inheritance: AD
• cerebroretinal microangiopathy with calcifications and cysts 3 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Tumor predisposition syndrome 3; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8; Cerebroretinal microangiopathy with calcifications and cysts 3	AD/AR	Allergy/Immunology/Infectious; Gastrointestinal; Hematologic; Oncologic; Pulmonary	For Tumor predisposition syndrome 3, awareness of risk of glioma and melanoma (as well as other malignancies) may allow surveillance and early disease detection and management; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related can involve hepatic manifestations, and awareness may allow early diagnosis and medical and surgical management; Surveillance and prompt treatment of findings related to bone marrow failure may reduce morbidity; For treatment related to pulmonary fibrosis, early recognition may allow prompt medical management; Cerebroretinal microangiopathy with calcifications and cysts can involve gastrointestinal ectasias wit hrisk of bleeding, and awareness may beneft medical management	Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Oncologic; Ophthalmologic; Pulmonary	24686846; 24686849; 25482530; 27013236; 35420632; 37140166
Susceptibility to cancer types other than melanoma and glioma has been suggested in the reported families with variants related to susceptibility to neoplasms

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the POT1 gene.

• Tumor predisposition syndrome 3 (1345 variants)
• Hereditary cancer-predisposing syndrome (882 variants)
• not provided (253 variants)
• not specified (111 variants)
• POT1-related condition (6 variants)
• Long telomere syndrome (5 variants)
• Glioma susceptibility 9;Tumor predisposition syndrome 3 (2 variants)
• Diffuse midline glioma, H3 K27-altered (1 variants)
• High-grade astrocytoma with piloid features (1 variants)
• Breast carcinoma (1 variants)
• Cerebroretinal microangiopathy with calcifications and cysts 3 (1 variants)
• Glioma susceptibility 9 (1 variants)
• Melanoma, cutaneous malignant, susceptibility to, 1 (1 variants)
• Glioma susceptibility 1;Melanoma, cutaneous malignant, susceptibility to, 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the POT1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	329	3	342
missense		2	813	10	2	827
nonsense	27	9	2			38
start loss	1	3				4
frameshift	52	8	5			65
inframe indel		1	16			17
splice donor/acceptor (+/-2bp)		30	4			34
splice region			66	65	2	133
non coding			20	190	48	258
Total	80	53	870	529	53

Highest pathogenic variant AF is 0.0000197

Variants in POT1

This is a list of pathogenic ClinVar variants found in the POT1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-124822455-T-C		not specified	Uncertain significance (May 27, 2016)
7-124822964-C-T			Benign (Dec 01, 2023)
7-124823873-T-C			Likely benign (Jun 23, 2018)
7-124823933-T-C		not specified	Likely benign (Aug 15, 2023)
7-124823965-G-C		Tumor predisposition syndrome 3	Uncertain significance (May 20, 2022)
7-124823965-G-T		Tumor predisposition syndrome 3	Likely benign (Feb 11, 2023)
7-124823966-A-G		Tumor predisposition syndrome 3	Uncertain significance (Sep 01, 2021)
7-124823968-T-G		Tumor predisposition syndrome 3	Likely benign (Oct 21, 2022)
7-124823968-TA-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Jul 05, 2023)
7-124823970-C-A		Hereditary cancer-predisposing syndrome	Likely benign (Feb 19, 2020)
7-124823971-A-C		Tumor predisposition syndrome 3	Uncertain significance (Oct 12, 2020)
7-124823971-A-G		Hereditary cancer-predisposing syndrome	Likely benign (Jun 04, 2021)
7-124823972-T-A		Tumor predisposition syndrome 3 • Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 22, 2024)
7-124823972-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 23, 2023)
7-124823976-C-T		Hereditary cancer-predisposing syndrome • Tumor predisposition syndrome 3	Uncertain significance (Dec 08, 2023)
7-124823977-T-C		Hereditary cancer-predisposing syndrome	Likely benign (Jun 02, 2022)
7-124823978-G-C		Tumor predisposition syndrome 3	Uncertain significance (Jun 10, 2023)
7-124823982-C-G		Tumor predisposition syndrome 3 • Hereditary cancer-predisposing syndrome	Uncertain significance (Jan 10, 2024)
7-124823982-CT-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Jul 02, 2020)
7-124823983-T-G		Tumor predisposition syndrome 3 • Hereditary cancer-predisposing syndrome • not specified	Benign (Feb 01, 2024)
7-124823985-T-C		Tumor predisposition syndrome 3	Uncertain significance (Jun 25, 2022)
7-124823986-G-C		Tumor predisposition syndrome 3	Likely benign (Jul 30, 2023)
7-124823986-G-T		Hereditary cancer-predisposing syndrome • Tumor predisposition syndrome 3	Likely benign (Aug 16, 2021)
7-124823987-G-A		Tumor predisposition syndrome 3	Uncertain significance (Aug 23, 2022)
7-124823987-G-T		Tumor predisposition syndrome 3	Uncertain significance (Sep 26, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
POT1	protein_coding	protein_coding	ENST00000357628	15	107598

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.853	0.147	125705	0	39	125744	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.92	226	323	0.699	0.0000158	4128
Missense in Polyphen		47	79.085	0.5943		955
Synonymous	-0.755	129	119	1.09	0.00000631	1197
Loss of Function	4.33	6	32.7	0.183	0.00000147	439

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000153	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000259	0.000255
Middle Eastern	0.000109	0.000109
South Asian	0.000102	0.0000980
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA- binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Binds to two or more telomeric single-stranded 5'-TTAGGG-3' repeats (G-strand) and with high specificity to a minimal telomeric single-stranded 5'- TAGGGTTAG-3' sequence. Binds telomeric single-stranded sequences internally or at proximity of a 3'-end. Its activity is TERT dependent but it does not increase TERT activity by itself. In contrast, the ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity. {ECO:0000269|PubMed:12768206, ECO:0000269|PubMed:12781132, ECO:0000269|PubMed:16166375, ECO:0000269|PubMed:17237768, ECO:0000269|PubMed:20231318}.
• Disease: DISEASE: Glioma 9 (GLM9) [MIM:616568]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:25482530}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Packaging Of Telomere Ends;Telomere Maintenance;Chromosome Maintenance;Cell Cycle;Regulation of Telomerase (Consensus)

Recessive Scores

• pRec: 0.162

Intolerance Scores

• loftool: 0.832
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.15

Haploinsufficiency Scores

• pHI: 0.169
• hipred: Y
• hipred_score: 0.714
• ghis: 0.582

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: N
• gene_indispensability_score: 0.309

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pot1a
• Phenotype: cellular phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype

Gene ontology

• Biological process: telomere maintenance via telomerase;telomere capping;telomere assembly;regulation of telomere maintenance via telomerase;negative regulation of telomere maintenance via telomerase;positive regulation of telomere maintenance via telomerase;DNA duplex unwinding;positive regulation of helicase activity;positive regulation of telomerase activity;negative regulation of telomerase activity;positive regulation of DNA strand elongation;telomeric D-loop disassembly;establishment of protein localization to telomere;regulation of DNA helicase activity;positive regulation of DNA helicase activity
• Cellular component: chromosome, telomeric region;nuclear telomere cap complex;nuclear chromosome, telomeric region;nucleus;nucleoplasm;shelterin complex
• Molecular function: protein binding;telomerase inhibitor activity;DEAD/H-box RNA helicase binding;telomeric DNA binding;single-stranded telomeric DNA binding;telomeric D-loop binding;telomeric G-quadruplex DNA binding;G-rich strand telomeric DNA binding;8-hydroxy-2'-deoxyguanosine DNA binding;G-rich single-stranded DNA binding