HGFAC

Chr 4

HGF activator

Also known as: HGFA

NCBI Gene: 3083 ENSG00000109758 UniProt: Q04756 OMIM: 604552

The protein is a serine protease that activates hepatocyte growth factor by converting it from an inactive precursor to its active form, initiating hepatocyte growth factor receptor signaling. Mutations cause autosomal recessive congenital factor XII deficiency, which presents as a bleeding disorder. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the peptidase S1 protein family. The encoded protein is first synthesized as an inactive single-chain precursor before being activated to a heterodimeric form by endoproteolytic processing. It acts as serine protease that converts hepatocyte growth factor to the active form. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.87

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.09

OE 0.58 (0.40–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.58Z-score

OE missense 1.08 (1.00–1.17)

458 obs / 424.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.58 (0.40–0.87)

0≤0.351.4

Missense OE?1.08 (1.00–1.17)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 17 / 29.2Missense obs/exp: 458 / 424.4Syn Z: -1.98

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

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

1,113 rare PASS variants

Rare truncating (LoF)

1 in 530

186 rare PASS variants

Rare synonymous (reference)

1 in 57

496 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HGFAC. 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 50	1 in 650
South Asian	~43k	1 in 35	1 in 780
Remaining (unassigned)	~30k	1 in 34	1 in 430
European (Finnish)	~26k	1 in 150	1 in 1,500
Admixed American	~22k	1 in 40	1 in 540
African / African American	~21k	1 in 38	1 in 480
East Asian	~20k	1 in 37	1 in 510
Ashkenazi Jewish	~13k	1 in 290	≈ 1 in 3,200
Middle Eastern	~2,883	1 in 35	1 in 380

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): 13 of 14 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 14.? see exons ↓