BAAT

protein-coding

bile acid-CoA:amino acid N-acyltransferase

Gene summary

The protein encoded by this gene is a liver enzyme that catalyzes the transfer of C24 bile acids from the acyl-CoA thioester to either glycine or taurine, the second step in the formation of bile acid-amino acid conjugates. The bile acid conjugates then act as a detergent in the gastrointestinal tract, which enhances lipid and fat-soluble vitamin absorption. Defects in this gene are a cause of familial hypercholanemia (FHCA). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001701.4

Inheritance

ClinVar variants

P:8U:110B:38

Top phenotype

Hypercholanemia, familial 3

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr9:101,354,182-101,385,400

External References & Databases

Ensembl (ENSG00000136881)

Transcript & Mutation Effects

hg38 • Region Span ~31.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial hypercholanemiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011905

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

bile acid CoA:amino acid N-acyltransferase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100305

Submitter: ClinGen

The relationship between BAAT and bile acid CoA:amino acid N-acyltransferase deficiency (also referred to as familial hypecholanemia in the literature), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of March, 2022. BAAT encodes a liver enzyme that is involved in the final step of bile acid synthesis, the conjugation of mature bile acids to glycine and taurine. This facilitates intestinal absorption of fats and fat-soluble vitamins. Patients with BAAT mutations show increased levels of unconjugated bile acids in the serum, urine and bile. They present with itching and fat malabsorption. BAAT was first reported in relation to autosomal recessive familial hypecholanemia in 2003 (Carlton et al, PMID: 12704386). The condition is also caused by mutations in genes other than BAAT. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (5.1 points): At least 10 patients in 4 publications have been reported with homozygous missense or nonsense variants (PMID: 12704386,10655068, 22783059, 23415802). The mechanism is expected to be homozygous loss of function. The variant segregated with disease in 5 additional family members. Summary of experimental data (2.5 points): This gene-disease association is supported by a mouse model originally developed by the IMPC project and later shown to recapitulate the biochemical deficiency (PMID: 21677750, PMID: 36243101). The enzyme is highly expressed in peroxisomes in hepatocytes (PMID: 17256745) and has a role in conjugating bile acids (PMID: 12810727). In summary, there is moderate level of evidence to support the gene-disease relationship of BAAT and bile acid CoA:amino acid N-acyltransferase deficiency. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP on Apr 9, 2022. It was reevaluated on May 3, 2024. As a result of this reevaluation, the classification did not change.

familial hypercholanemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011905

Submitter: Orphanet

hypercholanemia, familial 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031446

Submitter: Labcorp Genetics (formerly Invitae)

bile acid conjugation defect 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030991

Submitter: PanelApp Australia

bile acid conjugation defect 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030991

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypercholanemia, familial 3AR

Manifestation: Gastrointestinal; Hematologic

Intervention: Gastrointestinal; Hematologic

Rationale: Individuals may present with manifestations including pruritus, sequelae of fat malabsorption, failure to thrive, elevated serum bile acid concentrations, rickets, growth deficiency, and coagulopathy, which benefit from medical treatment (eg, ursodeoxycholic acid, fat-soluble vitamins, FFP and vitamin K, depending on the patient); Liver transplant has been described

Refs: 12704386; 22783059; 23415802

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BAAT variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 66

not providedTotal: 64

BAAT-related disorderTotal: 55

Hypercholanemia, familial 1Total: 21

Bile acid conjugation defect 1Total: 10

Hemolytic uremic syndrome, atypical, susceptibility to, 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001701.4. 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			13 clinvar	27 clinvar		40
missense	3 clinvar		91 clinvar	10 clinvar	1 clinvar	105
nonsense	1 clinvar	1 clinvar	2 clinvar			4
start loss			1 clinvar			1
frameshift		3 clinvar	3 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	4	4	110	37	1	156

Highest pathogenic variant AF is 0.000024161174

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001701.4	RefSeq	NP_001692.1	3	MANE Select
ENST00000259407.7	Ensembl	ENSP00000259407.2	3	MANE Select
NM_001127610.2	RefSeq	NP_001121082.1	3	Standard
NM_001374715.1	RefSeq	NP_001361644.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Bile secretion - Homo sapiens (human)
Peroxisome - Homo sapiens (human)
Biosynthesis of unsaturated fatty acids - Homo sapiens (human)
Taurine and hypotaurine metabolism - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)

Biological Process

liver development
bile acid conjugation
glycine metabolic process
protein targeting to peroxisome
fatty acid metabolic process

Molecular Function

signaling receptor binding
protein binding
palmitoyl-CoA hydrolase activity
N-acyltransferase activity
transferase activity, transferring acyl groups

Cellular Component

peroxisome
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259407
Coding exons: 3
Length: 23103
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125737
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0134	221	222	0.997	0.0000115	2696
Missense (PolyPhen)		57	75.642	0.75355		965
Synonymous	-0.546	92	85.6	1.08	0.00000446	868
Loss of Function	0.500	12	14.0	0.856	8.23e-7	162

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00033	0.00033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in bile acid metabolism. In liver hepatocytes catalyzes the second step in the conjugation of C24 bile acids (choloneates) to glycine and taurine before excretion into bile canaliculi. The major components of bile are cholic acid and chenodeoxycholic acid. In a first step the bile acids are converted to an acyl-CoA thioester, either in peroxisomes (primary bile acids deriving from the cholesterol pathway), or cytoplasmic at the endoplasmic reticulum (secondary bile acids). May catalyze the conjugation of primary or secondary bile acids, or both. The conjugation increases the detergent properties of bile acids in the intestine, which facilitates lipid and fat-soluble vitamin absorption. In turn, bile acids are deconjugated by bacteria in the intestine and are recycled back to the liver for reconjugation (secondary bile acids). May also act as an acyl-CoA thioesterase that regulates intracellular levels of free fatty acids. In vitro, catalyzes the hydrolysis of long- and very long-chain saturated acyl-CoAs to the free fatty acid and coenzyme A (CoASH), and conjugates glycine to these acyl-CoAs. {ECO:0000269|PubMed:12810727, ECO:0000269|PubMed:8034703}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.846
RVIS EVS: 0.71
RVIS percentile EVS: 85.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.256

Gene Damage Prediction

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