HMBS

Chr 11ARAD

hydroxymethylbilane synthase

Also known as: ENCEP, LENCEP, PBG-D, PBGD, PORC, UPS

This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviewsOMIMResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Encephalopathy, porphyria-relatedMIM #620704
AR
Leukoencephalopathy, porphyria-relatedMIM #620711
AR
Porphyria, acute intermittentMIM #176000
AD
Porphyria, acute intermittent, nonerythroid variantMIM #176000
AD

Clinical highlights

Gene-disease validity (ClinGen)
acute intermittent porphyria · SDDefinitivesufficient evidence for diagnostic panels
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.
1
Active trials
66
Pubs (1 yr)
P/LP submissions
P/LP missense
0.34
LOEUF· LoF intol.
LOF
Mechanism· predicted
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GeneReview available — HMBS
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint?
0.34LOEUF
pLI 0.949
Z-score 3.82
OE 0.13 (0.060.34)
Highly constrained

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

Missense Constraint?
0.64Z-score
OE missense 0.87 (0.770.99)
179 obs / 204.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.13 (0.060.34)
00.351.4
Missense OE?0.87 (0.770.99)
00.61.4
Synonymous OE?1.18
01.21.6
LoF obs/exp: 3 / 22.6Missense obs/exp: 179 / 204.9Syn Z: -1.23

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

HMBS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.