XRN1

Chr 3

5'-3' exoribonuclease 1

Also known as: SEP1

NCBI Gene: 54464 ENSG00000114127 UniProt: Q8IZH2 OMIM: 607994

This gene encodes a member of the 5'-3' exonuclease family. The encoded protein may be involved in replication-dependent histone mRNA degradation, and interacts directly with the enhancer of mRNA-decapping protein 4. In addition to mRNA metabolism, a similar protein in yeast has been implicated in a variety of nuclear and cytoplasmic functions, including homologous recombination, meiosis, telomere maintenance, and microtubule assembly. Mutations in this gene are associated with osteosarcoma, suggesting that the encoded protein may also play a role in bone formation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.20

Clinical Summary— XRN1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

174 VUS of 217 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 8.08

OE 0.12 (0.08–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.11Z-score

OE missense 0.80 (0.75–0.85)

693 obs / 867.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.08–0.20)

0≤0.351.4

Missense OE?0.80 (0.75–0.85)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 12 / 98.6Missense obs/exp: 693 / 867.7Syn Z: 0.74

This gene — mechanism propensity

0.3494th %ile

GOF

0.3491th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.20

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

ClinVar Variant Classifications

217 submitted variants in ClinVar

ClinVar

Classification Summary

VUS174

Likely Benign7

Benign1

174

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	174	0	0	174
Likely Benign	5	1	1	7
Benign	0	0	1	1
Total	179	1	2	182

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap XRN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →