rs1282394804

Variant names:

• chr11-108144009-A-G
• rs1282394804
• NM_000019.4:c.967A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_000019.4(ACAT1):​c.967A>G​(p.Ile323Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,123,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I323T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 4.93
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108144010-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 666517.
• PP5: Variant 11-108144009-A-G is Pathogenic according to our data. Variant chr11-108144009-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532307.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26060575). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAT1	NM_000019.4	c.967A>G	p.Ile323Val	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.967A>G	p.Ile323Val	missense_variant	Exon 10 of 12	1	NM_000019.4	ENSP00000265838.4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.0000116 AC: 13 AN: 1123086 Hom.: 0 Cov.: 42 AF XY: 0.00000892 AC XY: 5 AN XY: 560710

African (AFR) AF: 0.00 AC: 0 AN: 24990

American (AMR) AF: 0.00 AC: 0 AN: 37234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16360

East Asian (EAS) AF: 0.00 AC: 0 AN: 16598

South Asian (SAS) AF: 0.00 AC: 0 AN: 81980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.0000150 AC: 13 AN: 867982

Other (OTH) AF: 0.00 AC: 0 AN: 41216

GnomAD4 genome Cov.: 26

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Pathogenic:1 Uncertain:3

Dec 09, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Molecular Genetics, Istishari Arab Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We identified this missense variant (p.Ile323Val) in the homozygous state in six patients from three apparently unrelated families with clinical features consistent with beta-ketothiolase deficiency. Co-segregation with disease was observed in affected family members (PP1). To the best of our knowledge, this variant has not been previously reported in the literature. The variant is extremely rare in the general population (PM2) and results in an amino acid substitution at a residue where other pathogenic missense changes have been reported (ClinVar Variation ID: 666517) (PM5). In silico tools predict a deleterious effect (PolyPhen-2: 0.86; MutationTaster: polymorphism; CADD: 18.2; Alpha Missense Score: 0.77). In addition, missense varations are a common disease mechanism in ACAT1 (PP2). Based on this evidence, the variant is classified as likely pathogenic, consistent with ACMG criteria: PM2, PM5, PP1, PP2. -

Jan 06, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with valine at codon 323 of the ACAT1 protein (p.Ile323Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of ACAT1-related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Ile323 amino acid residue in ACAT1. Other variant(s) that disrupt this residue have been observed in individuals with ACAT1-related conditions (PMID: 27928777), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.011
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.47	N
PhyloP100		4.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.25
Sift	Benign	0.45	T
Sift4G	Benign	0.47	T
Polyphen		0.053	B
Vest4		0.36
MutPred		0.28		Loss of catalytic residue at I323 (P = 0.0841);
MVP		0.71
MPC		0.13
ClinPred		0.76	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.72
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1282394804; hg19: chr11-108014736;