rs120074147

Positions:

• chr11-108144039-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000019.4(ACAT1):​c.997G>C​(p.Ala333Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000191 in 1,569,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.46

Genes affected

ACAT1 (HGNC:93): (acetyl-CoA acetyltransferase 1) This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Defects in this gene are associated with 3-ketothiolase deficiency, an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and butanone. [provided by RefSeq, Feb 2009]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-108144039-G-C is Pathogenic according to our data. Variant chr11-108144039-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAT1	NM_000019.4	c.997G>C	p.Ala333Pro	missense_variant	10/12	ENST00000265838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT1	ENST00000265838.9	c.997G>C	p.Ala333Pro	missense_variant	10/12	1	NM_000019.4	P1
	ENST00000649165.1	n.535-1370C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00000699 AC: 1 AN: 143102 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426734 Hom.: 0 Cov.: 39 AF XY: 0.00000141 AC XY: 1 AN XY: 709770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000540

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000699 AC: 1 AN: 143102 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 69068

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000211

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 09, 2023	Variant summary: ACAT1 c.997G>C (p.Ala333Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR020617) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD, v2.1 Exomes dataset). c.997G>C has been reported in the literature in many compound heterozygous individuals, primarily of East Asian ancestry, affected with Alpha-Methylacetoacetic Aciduria (e.g., Fukao_1995, Fukao_1998, Su_2017, Lin_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant displayed no residual enzymatic activity (e.g., Fukao_1995, Fukao_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9744475, 7749408, 34001203, 28875337). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Gifu University	May 05, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2021	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 7749408). ClinVar contains an entry for this variant (Variation ID: 2845). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 9744475, 28875337; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs120074147, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 333 of the ACAT1 protein (p.Ala333Pro). -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.42	A
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.85
MutPred		0.92		Loss of helix (P = 0.0626);
MVP		0.95
MPC		0.28
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.96

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: rs120074147; hg19: chr11-108014766;