HACD3

Chr 15

3-hydroxyacyl-CoA dehydratase 3

Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May be involved in Rac1-signaling pathways leading to the modulation of gene expression. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571)

Research

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

0.59

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (3)

ncbi: TypeError: fetch failed

omim: Error: OMIM fetch failed: 429

trials: TypeError: fetch failed

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.009

Z-score 3.07

OE 0.33 (0.19–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.03Z-score

OE missense 0.79 (0.69–0.91)

153 obs / 193.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.19–0.59)

0≤0.351.4

Missense OE?0.79 (0.69–0.91)

0≤0.61.4

Synonymous OE?0.75

0≤1.21.6

LoF obs/exp: 8 / 24.3Missense obs/exp: 153 / 193.3Syn Z: 1.60

Background carrier burden — how many people carry a rare variant somewhere in HACD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

437 rare PASS variants

Rare truncating (LoF)

1 in 2,100

73 rare PASS variants

Rare synonymous (reference)

1 in 300

170 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HACD3. 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 2,000
South Asian	~43k	1 in 100	1 in 3,800
Remaining (unassigned)	~30k	1 in 150	1 in 1,500
European (Finnish)	~27k	1 in 380	none seen
Admixed American	~22k	1 in 110	≈ 1 in 21,000
African / African American	~21k	1 in 150	1 in 3,200
East Asian	~20k	1 in 110	1 in 1,200
Ashkenazi Jewish	~13k	1 in 840	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,800

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): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓