PNPT1

Chr 2ARAD

polyribonucleotide nucleotidyltransferase 1

Also known as: COXPD13, DFNB70, OLD35, PNPASE, SCA25, old-35

NCBI Gene: 87178 ENSG00000138035 UniProt: Q8TCS8 OMIM: 610316

The encoded protein is a 3'-to-5' exoribonuclease that localizes to the mitochondrial intermembrane space and facilitates RNA import into mitochondria. Mutations cause autosomal recessive combined oxidative phosphorylation deficiency-13, autosomal recessive nonsyndromic deafness (DFNB70) with or without adult-onset neurodegeneration, and autosomal dominant spinocerebellar ataxia 25. The pathogenic mechanism involves disrupted mitochondrial RNA processing and degradation leading to impaired oxidative phosphorylation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.473 OMIM phenotypes

Clinical Summary— PNPT1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

78 unique Pathogenic / Likely Pathogenic· 361 VUS of 1017 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.000

Z-score 4.56

OE 0.31 (0.21–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.42Z-score

OE missense 0.94 (0.86–1.02)

385 obs / 409.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.21–0.47)

0≤0.351.4

Missense OE?0.94 (0.86–1.02)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 16 / 51.2Missense obs/exp: 385 / 409.1Syn Z: -1.18

ClinVar Variant Classifications

1017 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39

Likely Pathogenic39

VUS361

Likely Benign434

Benign81

Conflicting33

Pathogenic

Likely Pathogenic

361

VUS

434

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	25	6	7	1	39
Likely Pathogenic	29	8	2	0	39
VUS	6	314	38	3	361
Likely Benign	1	7	267	159	434
Benign	0	2	75	4	81
Conflicting	—				33
Total	61	337	389	167	987

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap PNPT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →