PNPT1

polyribonucleotide nucleotidyltransferase 1

Basic information

Region (hg38): 2:55634060-55693863

Previous symbols: [ "DFNB70" ]

Links

ENSG00000138035 ∙ NCBI:87178 ∙ OMIM:610316 ∙ HGNC:23166 ∙ Uniprot:Q8TCS8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined oxidative phosphorylation defect type 13 (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 70 (Limited), mode of inheritance: AR
• combined oxidative phosphorylation defect type 13 (Definitive), mode of inheritance: AR
• combined oxidative phosphorylation defect type 13 (Strong), mode of inheritance: AR
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• spinocerebellar ataxia type 25 (Limited), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 70 (Limited), mode of inheritance: Unknown
• combined oxidative phosphorylation defect type 13 (Strong), mode of inheritance: AR
• Leigh syndrome (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Biochemical; Neurologic	23084290; 23084291; 30244537; 35411967

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PNPT1 gene.

• not provided (695 variants)
• not specified (43 variants)
• Combined oxidative phosphorylation defect type 13 (33 variants)
• Inborn genetic diseases (31 variants)
• Autosomal recessive nonsyndromic hearing loss 70 (23 variants)
• Combined oxidative phosphorylation defect type 13;Autosomal recessive nonsyndromic hearing loss 70 (5 variants)
• Spinocerebellar ataxia type 25 (4 variants)
• PNPT1-Related Disorders (3 variants)
• Global developmental delay (2 variants)
• Neurodevelopmental disorder (2 variants)
• PNPT1-related condition (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PNPT1 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	1		1	105	5	112
missense	2	5	245	9	2	263
nonsense	5	2	1			8
start loss						0
frameshift	7	3	2			12
inframe indel			5			5
splice donor/acceptor (+/-2bp)	1	8	2			11
splice region		1	24	34	8	67
non coding			7	160	63	230
Total	16	18	263	274	70

Highest pathogenic variant AF is 0.0000329

Variants in PNPT1

This is a list of pathogenic ClinVar variants found in the PNPT1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-55635931-TTCTA-T			Benign (Jun 14, 2018)
2-55635975-CTA-C			Benign (Jun 26, 2018)
2-55636078-A-T			Likely benign (Jul 08, 2018)
2-55636166-A-G			Benign (Jul 27, 2018)
2-55636225-T-TA		not specified • Combined oxidative phosphorylation defect type 13 • Autosomal recessive nonsyndromic hearing loss 70	Benign (Oct 25, 2021)
2-55636240-C-T			Likely benign (Sep 23, 2022)
2-55636240-CT-C			Uncertain significance (Jul 12, 2022)
2-55636244-G-C		Inborn genetic diseases	Uncertain significance (Nov 06, 2023)
2-55636253-G-A			Uncertain significance (Aug 03, 2022)
2-55636254-A-G			Uncertain significance (Aug 09, 2022)
2-55636255-T-C			Likely benign (Nov 28, 2022)
2-55636262-G-GAAAT			Uncertain significance (Mar 06, 2022)
2-55636268-G-A			Uncertain significance (Jul 20, 2022)
2-55636286-C-A			Uncertain significance (Oct 25, 2021)
2-55636288-A-G			Likely benign (Mar 10, 2023)
2-55636288-ACTT-A			Uncertain significance (Jun 28, 2022)
2-55636296-C-T		Inborn genetic diseases	Uncertain significance (Jan 22, 2024)
2-55636298-T-C			Uncertain significance (Nov 08, 2022)
2-55636311-C-G			Uncertain significance (Jul 30, 2022)
2-55636314-C-A			Uncertain significance (Jun 21, 2022)
2-55636314-C-T			Uncertain significance (Feb 10, 2022)
2-55636315-G-A			Likely benign (Dec 21, 2023)
2-55636315-G-T			Likely benign (Dec 13, 2021)
2-55636317-T-G			Uncertain significance (May 17, 2022)
2-55636318-T-G			Likely benign (Oct 05, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PNPT1	protein_coding	protein_coding	ENST00000447944	28	59646

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000401	1.00	125720	0	28	125748	0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.424	385	409	0.941	0.0000201	5029
Missense in Polyphen		102	131	0.7786		1622
Synonymous	-1.18	164	146	1.12	0.00000785	1518
Loss of Function	4.56	16	51.2	0.313	0.00000256	638

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000285	0.000277
Ashkenazi Jewish	0.00	0.00
East Asian	0.000165	0.000163
Finnish	0.0000946	0.0000924
European (Non-Finnish)	0.000126	0.000123
Middle Eastern	0.000165	0.000163
South Asian	0.0000665	0.0000653
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: RNA-binding protein implicated in numerous RNA metabolic processes. Catalyzes the phosphorolysis of single-stranded polyribonucleotides processively in the 3'-to-5' direction. Mitochondrial intermembrane factor with RNA-processing exoribonulease activity. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double- stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Required for correct processing and polyadenylation of mitochondrial mRNAs. Plays a role as a cytoplasmic RNA import factor that mediates the translocation of small RNA components, like the 5S RNA, the RNA subunit of ribonuclease P and the mitochondrial RNA-processing (MRP) RNA, into the mitochondrial matrix. Plays a role in mitochondrial morphogenesis and respiration; regulates the expression of the electron transport chain (ETC) components at the mRNA and protein levels. In the cytoplasm, shows a 3'-to-5' exoribonuclease mediating mRNA degradation activity; degrades c-myc mRNA upon treatment with IFNB1/IFN-beta, resulting in a growth arrest in melanoma cells. Regulates the stability of specific mature miRNAs in melanoma cells; specifically and selectively degrades miR-221, preferentially. Plays also a role in RNA cell surveillance by cleaning up oxidized RNAs. Binds to the RNA subunit of ribonuclease P, MRP RNA and miR-221 microRNA. {ECO:0000269|PubMed:12473748, ECO:0000269|PubMed:12721301, ECO:0000269|PubMed:12798676, ECO:0000269|PubMed:16055741, ECO:0000269|PubMed:16410805, ECO:0000269|PubMed:16934922, ECO:0000269|PubMed:18083836, ECO:0000269|PubMed:18083837, ECO:0000269|PubMed:18501193, ECO:0000269|PubMed:19509288, ECO:0000269|PubMed:20547861, ECO:0000269|PubMed:20691904}.
• Disease: DISEASE: Combined oxidative phosphorylation deficiency 13 (COXPD13) [MIM:614932]: A mitochondrial disorder characterized by early onset severe encephalomyopathy, dystonia, choreoathetosis, bucofacial dyskinesias and combined mitochondrial respiratory chain deficiency. Nerve conductions velocities are decreased. Levels of plasma and cerebrospinal fluid lactate are increased. {ECO:0000269|PubMed:23084291}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 70 (DFNB70) [MIM:614934]: A form of non-syndromic deafness characterized by severe, bilateral hearing impairment with prelingual onset, resulting in inability to acquire normal speech. {ECO:0000269|PubMed:23084290}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Pyrimidine metabolism - Homo sapiens (human);RNA degradation - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Pyrimidine metabolism;Purine metabolism;Pyrimidine metabolism (Consensus)

Recessive Scores

• pRec: 0.0952

Intolerance Scores

• loftool: 0.427
• rvis_EVS: 0.14
• rvis_percentile_EVS: 63.62

Haploinsufficiency Scores

• pHI: 0.231
• hipred: Y
• hipred_score: 0.540
• ghis: 0.562

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.915

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pnpt1
• Phenotype: skeleton phenotype; hematopoietic system 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); normal phenotype; cellular phenotype

Gene ontology

• Biological process: mitochondrial RNA catabolic process;mitochondrial mRNA catabolic process;positive regulation of mitochondrial RNA catabolic process;mitochondrial RNA processing;mitochondrial RNA 5'-end processing;mitochondrial RNA 3'-end processing;RNA catabolic process;mRNA catabolic process;cellular response to oxidative stress;cellular response to interferon-beta;RNA import into mitochondrion;rRNA import into mitochondrion;regulation of cellular respiration;RNA polyadenylation;negative regulation of growth;protein homooligomerization;response to cAMP;response to growth hormone;positive regulation of mRNA catabolic process;protein homotrimerization;mitochondrion morphogenesis;nuclear polyadenylation-dependent mRNA catabolic process;mitotic cell cycle arrest;RNA phosphodiester bond hydrolysis, exonucleolytic;mitochondrial mRNA polyadenylation;liver regeneration;positive regulation of miRNA catabolic process;regulation of cellular senescence
• Cellular component: nucleus;cytoplasm;mitochondrion;mitochondrial intermembrane space;endoplasmic reticulum membrane;cytosol;polysomal ribosome;mitochondrial degradosome
• Molecular function: 3'-5'-exoribonuclease activity;RNA binding;polyribonucleotide nucleotidyltransferase activity;protein binding;poly(U) RNA binding;poly(G) binding;miRNA binding