11-108138934-A-G

Position:

chr11-108138934-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000019.4(ACAT1):c.472A>G(p.Asn158Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,614,030 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ACAT1
NM_000019.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.60

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 11-108138934-A-G is Pathogenic according to our data. 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. Variant chr11-108138934-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAT1	NM_000019.4 linkuse as main transcript	c.472A>G	p.Asn158Asp	missense_variant	6/12	ENST00000265838.9	NP_000010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAT1	ENST00000265838.9 linkuse as main transcript	c.472A>G	p.Asn158Asp	missense_variant	6/12	1	NM_000019.4	ENSP00000265838	P1	P24752-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251414

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000656

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000447

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2021	Variant summary: ACAT1 c.472A>G (p.Asn158Asp) results in a conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) and at the dimer interface (Abdelkreem_2019) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251414 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACAT1 causing Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (6e-05 vs 0.0029), allowing no conclusion about variant significance. c.472A>G has been reported in the literature in individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (Fukao_1995, Sakurai_2007, Otsuka_2016, Wojcik_2017). These data indicate that the variant is likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in reduced activity (Fukao_1995, Wakazono_1995, Sakurai_2007). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for 3-ketothiolase deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/7728148). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 158 of the ACAT1 protein (p.Asn158Asp). This variant is present in population databases (rs148639841, gnomAD 0.01%). This missense change has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 7749408, 17236799, 27748876). ClinVar contains an entry for this variant (Variation ID: 92297). 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). 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: 17236799, 21669895). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Gifu University	May 05, 2019	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2019	Published in vivo expression analysis showed no residual enzyme activity (Fukao et al., 1995); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25087612, 7749408, 7728148, 27748876) -

ACAT1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

The ACAT1 c.472A>G variant is predicted to result in the amino acid substitution p.Asn158Asp. This variant has been reported with a second pathogenic variant in four affected individuals (Fukao et al. 1995. PubMed ID: 7749408; Sakurai et al. 2007. PubMed ID: 17236799; Otsuka et al. 2016. PubMed ID: 27748876). In vitro functional studies found the p.Asn158Asp substitution resulted in a protein with no residual activity (Fukao et al. 1995. PubMed ID: 7749408; Sakurai et al. 2007. PubMed ID: 17236799). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.0054

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.016

Polyphen

0.93

Vest4

0.92

MVP

0.93

MPC

0.53

ClinPred

0.65

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over