LEO1

Chr 15

LEO1 component of Paf1/RNA polymerase II complex

Also known as: RDL

NCBI Gene: 123169 ENSG00000166477 UniProt: Q8WVC0 OMIM: 610507

LEO1, parafibromin (CDC73; MIM 607393), CTR9 (MIM 609366), and PAF1 (MIM 610506) form the PAF protein complex that associates with the RNA polymerase II subunit POLR2A (MIM 180660) and with a histone methyltransferase complex (Rozenblatt-Rosen et al., 2005 [PubMed 15632063]).[supplied by OMIM, Mar 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.871

Z-score 4.62

OE 0.19 (0.10–0.35)

Highly constrained

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

Missense Constraint?

2.34Z-score

OE missense 0.66 (0.59–0.73)

241 obs / 367.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.35)

0≤0.351.4

Missense OE?0.66 (0.59–0.73)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 7 / 37.5Missense obs/exp: 241 / 367.5Syn Z: 0.64

Background carrier burden — how many people carry a rare variant somewhere in LEO1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

680 rare PASS variants

Rare truncating (LoF)

1 in 6,700

63 rare PASS variants

Rare synonymous (reference)

1 in 190

282 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LEO1. 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 170	1 in 9,700
South Asian	~43k	1 in 75	1 in 5,400
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 7,400
European (Finnish)	~27k	1 in 250	1 in 3,300
Admixed American	~22k	1 in 160	≈ 1 in 21,000
African / African American	~21k	1 in 69	≈ 1 in 6,400
East Asian	~20k	1 in 100	≈ 1 in 4,900
Ashkenazi Jewish	~13k	1 in 520	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 120	≈ 1 in 2,900

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): 9 of 12 coding exons well covered in gnomAD exomes; exons 4, 6, 12 marginal. Genomes: all 12.? see exons ↓