rs199524907

chr11-108138935-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000019.4(ACAT1):c.473A>G(p.Asn158Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N158D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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_000019.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108138934-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-108138935-A-G is Pathogenic according to our data. Variant chr11-108138935-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33567393).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAT1	NM_000019.4	c.473A>G	p.Asn158Ser	missense_variant	6/12	ENST00000265838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT1	ENST00000265838.9	c.473A>G	p.Asn158Ser	missense_variant	6/12	1	NM_000019.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251402 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000142 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2020	Variant summary: ACAT1 c.473A>G (p.Asn158Ser) results in a conservative amino acid change located in the Thiolase, N-terminal of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251402 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACAT1 causing Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (0.00031 vs 0.0029), allowing no conclusion about variant significance. c.473A>G has been reported in the literature in individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency and has been subsequently cited by others (example, Sakurai_2007, Sarafoglou_2011, Abdelkreem_2019). 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 (Sakurai_2007). The most pronounced variant effect results in a loss of catalytic activity due to an inability to fold into a tetramer configuration essential for the tertiary structure. A different missense substitution (p.Asn158Asp) at this location has been reported in patients with this disorder further corroborating a critical role of the Aspargine residue for protein function. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 158 of the ACAT1 protein (p.Asn158Ser). This variant is present in population databases (rs199524907, gnomAD 0.2%). This missense change has been observed in individual(s) with acetoacetyl-CoA-thiolase deficiency (PMID: 17236799, 21669895). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 198030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACAT1 protein function. Experimental studies have shown that this missense change affects ACAT1 function (PMID: 17236799, 21669895). This variant disrupts the p.Asn158 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7749408, 17236799, 27748876). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2023	The ACAT1 c.473A>G; p.Asn158Ser variant (rs199524907), is reported in the literature in three individuals affected with alpha-methylacetoacetic aciduria (Abdelkreem 2019, Sakurai 2007, Sarafoglou 2011). This variant is also reported in ClinVar (Variation ID: 198030). This variant is found in the general population with an allele frequency of 0.03% (81/282788 alleles) in the Genome Aggregation Database. Additionally, another amino acid substitution at this codon (c.472A>G; p.Asn158Asp) has been reported in individuals with alpha-methylacetoacetic aciduria and is considered likely pathogenic (Otsuka 2016, Sakura 2007, Wakazono 1995). Functional analysis of the variant protein show a loss of catalytic activity (Abdelkreem 2019, Sakurai 2007). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.524). Based on available information, the c.473A>G; p.Asn158Ser variant is considered to be likely pathogenic. References: Abdelkreem E et al. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Hum Mutat. 2019 Oct;40(10):1641-1663. PMID: 31268215. Otsuka H et al. Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site. Mol Med Rep. 2016 Nov;14(5):4906-4910. PMID: 27748876. Sakurai S et al. Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure. Mol Genet Metab. 2007 Apr;90(4):370-8. PMID: 17236799. Sarafoglou K et al. Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics. 2011 Jul;128(1):e246-50. PMID: 21669895. Wakazono et al. Molecular, biochemical, and clinical characterization of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in two further patients. Hum Mutat. 1995;5(1):34-42. PMID: 7728148. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that N158S was associated with temperature sensitive instability, with faint to no detection of mutant protein at different temperatures as compared to wild-type protein (Sakurai et al., 2007).; This variant is associated with the following publications: (PMID: 17236799, 21669895, 31268215) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2014	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2021

The c.473A>G (p.N158S) alteration is located in exon 6 (coding exon 6) of the ACAT1 gene. This alteration results from a A to G substitution at nucleotide position 473, causing the asparagine (N) at amino acid position 158 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD) database, the ACAT1 c.473A>G alteration was observed in 0.03% (81/282788) of total alleles studied, with a frequency of 0.22% (78/35438) in the Latino subpopulation. This alteration has been reported in the compound heterozygous state with another alteration in patients with clinical and biochemical features of alpha-methylacetoacetic aciduria (Sakurai, 2007; Sarafoglou, 2011). In addition, another pathogenic mutation (p.N158D) has been reported affecting the same amino acid position (Sakurai, 2007). Based on transient expression analysis of mutant cDNA, the N158S alteration demonstrated protein instability in a temperature-sensitive manner and no residual enzyme activity (Sakurai, 2007). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.023	D
Sift4G	Benign	0.074	T
Polyphen		0.80	P
Vest4		0.88
MVP		0.91
MPC		0.23
ClinPred		0.74	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199524907; hg19: chr11-108009662;