HSD3B7

protein-coding

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

This gene encodes an enzyme which is involved in the initial stages of the synthesis of bile acids from cholesterol and a member of the short-chain dehydrogenase/reductase superfamily. The encoded protein is a membrane-associated endoplasmic reticulum protein which is active against 7-alpha hydrosylated sterol substrates. Mutations in this gene are associated with a congenital bile acid synthesis defect which leads to neonatal cholestasis, a form of progressive liver disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

MANE transcript

NM_025193.4

Inheritance

ClinVar variants

P:32U:112B:55

Top phenotype

Bile acid synthesis defect, congenital, 1

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr16:30,985,207-30,989,147

External References & Databases

Ensembl (ENSG00000099377)

Transcript & Mutation Effects

hg38 • Region Span ~3.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital bile acid synthesis defect 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011906

Submitter: G2P

congenital bile acid synthesis defect 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011906

Submitter: ClinGen

*HSD3B7* was first reported in relation to autosomal recessive congenital bile acid synthesis defect 1 in 2000 (Schwarz M, et al., 2000, PMID: 11067870). The 3β-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids and HSD VII is active against four 7-alpha-hydroxylated sterols. The deficiency of 3β-HSD causes congenital defects of bile acid synthesis, characterized by neonatal onset of progressive liver disease with cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract resulting from a primary failure to synthesize bile acids. Affected infants show failure to thrive and secondary coagulopathy. At least 53 cases of 3β-HSD have been reported (reviewed in PMID: 26080666), with six variants (missense, frameshift, and nonsense) from 6 probands (and 1 additional family member) in 2 publications (PMIDs: 11067870, 12679481) included here. This gene-disease association is also supported by its biochemical functions in bile acid synthesis and enriched expression in the liver (PMID: 11067870). Additionally, a knockout mouse model that recapitulates human phenotype (PMID: 17601774). In summary, *HSD3B7* is definitively associated with autosomal recessive congenital bile acid synthesis defect 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

congenital bile acid synthesis defect 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011906

Submitter: Orphanet

congenital bile acid synthesis defect 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011906

Submitter: Labcorp Genetics (formerly Invitae)

congenital bile acid synthesis defect 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011906

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Bile acid synthesis defect, congenital, 1AR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal

Rationale: Due to early-onset progressive hepatic disease, affected invididuals commonly present in infancy with failure to thrive and coagulopathy, and typically demonstrate a favorable response to medical treatment (with oral bile acid therapy)

Refs: 3470305; 11067870; 12679481; 22095780

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HSD3B7 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 115

HSD3B7-related disorderTotal: 76

Inborn genetic diseasesTotal: 68

Congenital bile acid synthesis defect 1Total: 24

not specifiedTotal: 11

Congenital bile acid synthesis defectTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025193.4. 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			5 clinvar	46 clinvar	2 clinvar	53
missense		5 clinvar	105 clinvar	6 clinvar	1 clinvar	117
nonsense	3 clinvar	3 clinvar				6
start loss						0
frameshift	9 clinvar	4 clinvar				13
splice donor/acceptor (+/-2bp)	3 clinvar	5 clinvar	2 clinvar			10
Total	15	17	112	52	3	199

Highest pathogenic variant AF is 0.00007459059

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025193.4	RefSeq	NP_079469.2	6	MANE Select
ENST00000297679.10	Ensembl	ENSP00000297679.5	6	MANE Select
NM_001142777.2	RefSeq	NP_001136249.1	5	Standard
NM_001142778.2	RefSeq	NP_001136250.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary bile acid biosynthesis - Homo sapiens (human)
27-Hydroxylase Deficiency
Bile Acid Biosynthesis
Congenital Bile Acid Synthesis Defect Type II
Cerebrotendinous Xanthomatosis (CTX)

Biological Process

bile acid biosynthetic process
cholesterol catabolic process
B cell chemotaxis
oxidation-reduction process

Molecular Function

3-beta-hydroxy-delta5-steroid dehydrogenase activity
protein binding
oxidoreductase activity
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
cholest-5-ene-3-beta,7-alpha-diol 3-beta-dehydrogenase activity

Cellular Component

cellular_component
endoplasmic reticulum membrane
lipid droplet
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000297679
Coding exons: 6
Length: 3955
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125747
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.768	202	235	0.859	0.0000166	2303
Missense (PolyPhen)		73	84.065	0.86837		858
Synonymous	1.10	91	105	0.864	0.00000754	810
Loss of Function	0.590	13	15.5	0.838	7.67e-7	157

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00024	0.00023	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids. HSD VII is active against four 7-alpha-hydroxylated sterols. Does not metabolize several different C(19/21) steroids as substrates. Involved in bile acid synthesis (PubMed:11067870). Plays a key role in cell positioning and movement in lymphoid tissues by mediating degradation of 7-alpha,25-dihydroxycholesterol (7- alpha,25-OHC): 7-alpha,25-OHC acts as a ligand for the G protein- coupled receptor GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells. {ECO:0000250|UniProtKB:Q9EQC1, ECO:0000269|PubMed:11067870}.;
Disease: DISEASE: Congenital bile acid synthesis defect 1 (CBAS1) [MIM:607765]: A primary defect in bile synthesis leading to progressive liver disease. Clinical features include neonatal jaundice, severe intrahepatic cholestasis, cirrhosis. {ECO:0000269|PubMed:11067870, ECO:0000269|PubMed:12679481}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.173

Intolerance Scores

LoFtool: 0.167
RVIS EVS: -0.2
RVIS percentile EVS: 39.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.748

Gene Damage Prediction

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