HSD17B3

Chr 9AR

hydroxysteroid 17-beta dehydrogenase 3

Also known as: EDH17B3, SDR12C2

NCBI Gene: 3293 ENSG00000130948 UniProt: P37058

This isoform of 17 beta-hydroxysteroid dehydrogenase is expressed predominantly in the testis and catalyzes the conversion of androstenedione to testosterone. It preferentially uses NADP as cofactor. Deficiency can result in male pseudohermaphroditism with gynecomastia. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Pseudohermaphroditism, male, with gynecomastiaMIM #264300

UniProtMale pseudohermaphrodism with gynecomastia

Active trials

103

Pathogenic / LP

389

ClinVar variants

Pubs (1 yr)

0.4

Missense Z

1.09

LOEUF

Clinical Summary— HSD17B3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

103 Pathogenic / Likely Pathogenic· 67 VUS of 389 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

1.09LOEUF

pLI 0.000

Z-score 1.28

OE 0.67 (0.43–1.09)

Tolerant

Highly tolerant — LoF variants common in population

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.

0.37Z-score

OE missense 0.92 (0.81–1.05)

155 obs / 168.4 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.0.67 (0.43–1.09)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.81–1.05)

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.0.91

0≤1.21.6

LoF obs/exp: 12 / 17.8Missense obs/exp: 155 / 168.4Syn Z: 0.57

0.86top 5%

GOF

0.6542th %ile

LOF

0.1796th %ile

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

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.