HSD17B3

protein-coding

hydroxysteroid 17-beta dehydrogenase 3, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

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]

MANE transcript

NM_000197.2

Inheritance

ClinVar variants

P:68U:57B:78

Top phenotype

17-Beta hydroxysteroid dehydrogenase III deficiency

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr9:96,235,306-96,302,176

External References & Databases

Ensembl (ENSG00000130948)

Transcript & Mutation Effects

hg38 • Region Span ~66.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009916

Submitter: PanelApp Australia

46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009916

Submitter: Orphanet

46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009916

Submitter: Ambry Genetics

46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009916

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

17-Beta hydroxysteroid dehydrogenase III deficiencyAR

Manifestation: Endocrine; Genitourinary

Intervention: Endocrine; Genitourinary

Rationale: Prepubertal diagnosis may allow surgical treatment via removal of abnormal testes, preventing typical presenting clinical signs in puberty (marked masculinization and hirsutism)

Refs: 2998649; 8075637; 8550739; 10599740; 21700882; 22212252; 22594312; 22445608; 22876557

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HSD17B3 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 243

Testosterone 17-beta-dehydrogenase deficiencyTotal: 71

Inborn genetic diseasesTotal: 28

HSD17B3-related disorderTotal: 17

not specifiedTotal: 14

PseudohermaphroditismTotal: 13

Differences in sex developmentTotal: 5

Disorder of sexual differentiationTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000197.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	72 clinvar	1 clinvar	75
missense	7 clinvar	21 clinvar	50 clinvar	4 clinvar	1 clinvar	83
nonsense	5 clinvar	4 clinvar	1 clinvar			10
start loss		3 clinvar	1 clinvar			4
frameshift	9 clinvar	5 clinvar	2 clinvar			16
splice donor/acceptor (+/-2bp)	8 clinvar	6 clinvar	1 clinvar			15
Total	29	39	57	76	2	203

Highest pathogenic variant AF is 0.0006124633

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000197.2	RefSeq	NP_000188.1	11	MANE Select
ENST00000375263.8	Ensembl	ENSP00000364412.3	11	MANE Select
ENST00000375262.4	Ensembl	ENSP00000364411.2	10	Standard
ENST00000467499.6	Ensembl	ENSP00000498077.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid hormone biosynthesis - Homo sapiens (human)
17-Beta Hydroxysteroid Dehydrogenase III Deficiency
Androgen and Estrogen Metabolism
Aromatase deficiency
Androgen Receptor Network in Prostate Cancer

Biological Process

steroid biosynthetic process
androgen biosynthetic process
male genitalia development
oxidation-reduction process
testosterone biosynthetic process

Molecular Function

testosterone dehydrogenase [NAD(P)] activity
testosterone 17-beta-dehydrogenase (NADP+) activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375263
Coding exons: 11
Length: 66847
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.367	155	168	0.920	0.00000966	2001
Missense (PolyPhen)		49	53.89	0.90927		664
Synonymous	0.568	63	69.0	0.913	0.00000446	613
Loss of Function	1.28	12	17.8	0.673	7.76e-7	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Favors the reduction of androstenedione to testosterone. Uses NADPH while the two other EDH17B enzymes use NADH. {ECO:0000269|PubMed:26545797}.;

Recessive Scores

pRec: 0.219

Intolerance Scores

LoFtool: 0.229
RVIS EVS: -0.16
RVIS percentile EVS: 42.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0330

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium