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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

LOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in XRN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 40

1,842 rare PASS variants

Rare truncating (LoF)

1 in 1,400

163 rare PASS variants

Rare synonymous (reference)

1 in 94

696 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for XRN1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 52	1 in 1,400
South Asian	~43k	1 in 29	1 in 1,900
Remaining (unassigned)	~30k	1 in 38	1 in 720
European (Finnish)	~27k	1 in 170	1 in 3,800
Admixed American	~22k	1 in 43	1 in 1,100
African / African American	~21k	1 in 34	1 in 1,000
East Asian	~20k	1 in 42	1 in 1,500
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 52	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 37 of 41 coding exons well covered in gnomAD exomes; exons 6, 28, 30, 32 marginal. Genomes: all 41.? see exons ↓