9-101371179-T-G

Position:

• chr9-101371179-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001701.4(BAAT):​c.226A>C​(p.Met76Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M76V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAAT NM_001701.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

Genes affected

BAAT (HGNC:932): (bile acid-CoA:amino acid N-acyltransferase) 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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001701.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-101371179-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6720.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAAT	NM_001701.4	c.226A>C	p.Met76Leu	missense_variant	2/4	ENST00000259407.7
BAAT	NM_001127610.2	c.226A>C	p.Met76Leu	missense_variant	2/4
BAAT	NM_001374715.1	c.226A>C	p.Met76Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAAT	ENST00000259407.7	c.226A>C	p.Met76Leu	missense_variant	2/4	1	NM_001701.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.90		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.80
MPC		0.31
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.89
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28937579; hg19: chr9-104133461;