rs120074147

Variant names:

• chr11-108144039-G-C
• rs120074147
• NM_000019.4:c.997G>C

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 7 publications found

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]

ACAT1 Gene-Disease associations (from GenCC):

• beta-ketothiolase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, Ambry Genetics

ENSG00000285696 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 2845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAT1	NM_000019.4	c.997G>C	p.Ala333Pro	missense_variant	Exon 10 of 12	ENST00000265838.9	NP_000010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAT1	ENST00000265838.9	c.997G>C	p.Ala333Pro	missense_variant	Exon 10 of 12	1	NM_000019.4	ENSP00000265838.4

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

African (AFR) AF: 0.00 AC: 0 AN: 32098

American (AMR) AF: 0.00 AC: 0 AN: 43572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24718

East Asian (EAS) AF: 0.0000540 AC: 2 AN: 37038

South Asian (SAS) AF: 0.00 AC: 0 AN: 85884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5556

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089600

Other (OTH) AF: 0.00 AC: 0 AN: 57832

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

African (AFR) AF: 0.00 AC: 0 AN: 37990

American (AMR) AF: 0.00 AC: 0 AN: 13806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.000211 AC: 1 AN: 4730

South Asian (SAS) AF: 0.00 AC: 0 AN: 4488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66766

Other (OTH) AF: 0.00 AC: 0 AN: 1930

Alfa AF: 0.00 Hom.: 0

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

Jan 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 05, 2019

Department of Pediatrics, Gifu University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Dec 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects ACAT1 function (PMID: 7749408). 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). This variant is present in population databases (rs120074147, gnomAD 0.06%). 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. ClinVar contains an entry for this variant (Variation ID: 2845). 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.

Sep 05, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		6.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.85
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.96
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs120074147; hg19: chr11-108014766;