HGF

Chr 7AR

hepatocyte growth factor

Also known as: DFNB39, F-TCF, HGFB, HPTA, SF

NCBI Gene: 3082 ENSG00000019991 UniProt: P14210 OMIM: 142409

The HGF protein is a secreted cytokine that binds to the hepatocyte growth factor receptor (MET) to regulate cell growth, motility, and morphogenesis across multiple tissue types. Mutations cause autosomal recessive nonsyndromic hearing loss (deafness, autosomal recessive 39). The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.25), indicating that biallelic mutations resulting in severe protein dysfunction are likely required for disease manifestation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss. [provided by RefSeq, Nov 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 39MIM #608265

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · nonsyndromic genetic hearing loss · AR · ClinGen 2024

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

868

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — HGF

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.999

Z-score 5.82

OE 0.13 (0.07–0.25)

Highly constrained

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

Missense Constraint?

1.85Z-score

OE missense 0.74 (0.68–0.82)

305 obs / 410.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.25)

0≤0.351.4

Missense OE?0.74 (0.68–0.82)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 7 / 52.6Missense obs/exp: 305 / 410.2Syn Z: -0.67

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 94

814 rare PASS variants

Rare truncating (LoF)

1 in 2,300

74 rare PASS variants

Rare synonymous (reference)

1 in 240

319 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HGF. 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 110	1 in 2,200
South Asian	~43k	1 in 86	1 in 3,100
Remaining (unassigned)	~30k	1 in 100	1 in 3,800
European (Finnish)	~27k	1 in 200	≈ 1 in 8,900
Admixed American	~22k	1 in 110	1 in 2,800
African / African American	~21k	1 in 110	≈ 1 in 5,900
East Asian	~20k	1 in 80	1 in 1,000
Ashkenazi Jewish	~13k	1 in 300	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 90	none seen

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): 11 of 18 coding exons well covered in gnomAD exomes; exon 12 poorly covered; exons 2, 3, 4, 10, 14, 16 marginal. Genomes: all 18.? see exons ↓