EXO1

Chr 1

exonuclease 1

Also known as: HEX1, hExoI

NCBI Gene: 9156 ENSG00000174371 UniProt: Q9UQ84 OMIM: 606063

This gene encodes a 5' to 3' exonuclease that functions in DNA mismatch repair, somatic hypermutation of immunoglobulin genes, and is essential for meiosis. Mutations cause autosomal recessive endometrial cancer predisposition and are associated with hereditary nonpolyposis colorectal cancer susceptibility. The gene shows very low constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein with 5' to 3' exonuclease activity as well as an RNase H activity. It is similar to the Saccharomyces cerevisiae protein Exo1 which interacts with Msh2 and which is involved in mismatch repair and recombination. Alternative splicing of this gene results in three transcript variants encoding two different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Refuted · Lynch syndrome · AD · ClinGen 2023

evidence has disproved this relationship

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.93

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.92

OE 0.66 (0.48–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.03Z-score

OE missense 1.14 (1.06–1.23)

500 obs / 439.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.66 (0.48–0.93)

0≤0.351.4

Missense OE?1.14 (1.06–1.23)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 25 / 37.7Missense obs/exp: 500 / 439.1Syn Z: -0.86

Background carrier burden — how many people carry a rare variant somewhere in EXO1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 33

1,123 rare PASS variants

Rare truncating (LoF)

1 in 650

187 rare PASS variants

Rare synonymous (reference)

1 in 150

398 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EXO1. 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 54	1 in 790
South Asian	~43k	1 in 37	1 in 620
Remaining (unassigned)	~30k	1 in 32	1 in 970
European (Finnish)	~27k	1 in 130	1 in 340
Admixed American	~22k	1 in 39	1 in 830
African / African American	~21k	1 in 39	1 in 380
East Asian	~20k	1 in 53	1 in 400
Ashkenazi Jewish	~13k	1 in 210	1 in 1,200
Middle Eastern	~2,884	1 in 52	1 in 210

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 13 coding exons well covered in gnomAD exomes; exons 5, 10, 14 marginal. Genomes: all 13.? see exons ↓