HNF1A

Chr 12ARAD

HNF1 homeobox A

Also known as: HNF-1-alpha, HNF-1A, HNF1, HNF1alpha, IDDM20, LFB1, MODY3, TCF-1

NCBI Gene: 6927 ENSG00000135100 UniProt: P20823

The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

Primary Disease Associations & Inheritance

{Diabetes mellitus, insulin-dependent}MIM #222100

{Diabetes mellitus, noninsulin-dependent, 2}MIM #125853

Diabetes mellitus, insulin-dependent, 20MIM #612520

Hepatic adenoma, somaticMIM #142330

MODY, type IIIMIM #600496

Renal cell carcinomaMIM #144700

UniProtHepatic adenomas familial

UniProtMaturity-onset diabetes of the young 3

UniProtType 1 diabetes mellitus 20

Active trials

150

Pathogenic / LP

494

ClinVar variants

Pubs (1 yr)

1.1

Missense Z

0.33

LOEUF· LoF intolerant

Clinical Summary— HNF1A

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Gene-Disease Validity (ClinGen)

monogenic diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

150 Pathogenic / Likely Pathogenic· 195 VUS of 494 total submissions

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — HNF1A

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?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.33LOEUF

pLI 0.961

Z-score 4.18

OE 0.14 (0.07–0.33)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.14Z-score

OE missense 0.84 (0.76–0.92)

318 obs / 380.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.14 (0.07–0.33)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.76–0.92)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.14

0≤1.21.6

LoF obs/exp: 4 / 27.8Missense obs/exp: 318 / 380.3Syn Z: -1.42

0.3892th %ile

GOF

0.3193th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 47% of P/LP variants are LoF · LOEUF 0.33

DN1 literature citation

Literature Evidence

DNThe mutation causes a dominant-negative HNF1A protein variant which blocks HNF1A wild-type-mediated gene expression.The novel Q495X mutation is the likely cause of our patient's diabetes and hepatic adenomatosis.PMID:23616187

LOFHeterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY).PMID:32001615

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.