PARN

Chr 16ARAD

poly(A)-specific ribonuclease

Also known as: DAN, DKCB6, PFBMFT4

NCBI Gene: 5073 ENSG00000140694 UniProt: O95453 OMIM: 604212

The protein is a 3'-exoribonuclease that degrades poly(A) tails of mRNAs, representing the first step in mRNA decay, and is also involved in nonsense-mediated decay and silencing of maternal mRNAs during early development. Mutations cause dyskeratosis congenita and pulmonary fibrosis with bone marrow failure syndrome, both telomere-related disorders with autosomal recessive inheritance. The gene is highly intolerant to loss-of-function variants (LOEUF 0.52), reflecting its essential role in RNA metabolism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a 3'-exoribonuclease, with similarity to the RNase D family of 3'-exonucleases. It prefers poly(A) as the substrate, hence, efficiently degrades poly(A) tails of mRNAs. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. This protein is also involved in silencing of certain maternal mRNAs during oocyte maturation and early embryonic development, as well as in nonsense-mediated decay (NMD) of mRNAs that contain premature stop codons. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.522 OMIM phenotypes

Clinical Summary— PARN

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Gene-Disease Validity (ClinGen)

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

100 unique Pathogenic / Likely Pathogenic· 456 VUS of 998 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PARN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 4.02

OE 0.33 (0.22–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.79Z-score

OE missense 0.88 (0.79–0.97)

285 obs / 325.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.22–0.52)

0≤0.351.4

Missense OE?0.88 (0.79–0.97)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 14 / 42.2Missense obs/exp: 285 / 325.3Syn Z: 0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePARN-related dyskeratosis congenitaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5575th %ile

GOF

0.4085th %ile

LOF

0.3647th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFWe found an additional new missense variant (encoding p.Lys421Arg) in a proband of European ancestry. PARN is among the 20% of genes with the lowest prevalence of rare variants that are likely to disrupt normal function (mutation-intolerant genes)14, consistent with the identified variants causing h1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 25848748 ↗

ClinVar Variant Classifications

998 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54

Likely Pathogenic46

VUS456

Likely Benign369

Benign32

Conflicting15

Pathogenic

Likely Pathogenic

456

VUS

369

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	44	0	10	0	54
Likely Pathogenic	36	2	8	0	46
VUS	9	388	51	8	456
Likely Benign	0	2	221	146	369
Benign	0	2	30	0	32
Conflicting	—				15
Total	89	394	320	154	972

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap PARN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →