11-108140107-C-G

Variant names:

• chr11-108140107-C-G
• rs532190594
• NM_000019.4:c.622C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000019.4(ACAT1):​c.622C>G​(p.Arg208Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82
• Publications: 16 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108140108-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198381.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000019.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	NM_000019.4	MANE Select	c.622C>G	p.Arg208Gly	missense	Exon 7 of 12	NP_000010.1
	ACAT1	NM_001386677.1		c.622C>G	p.Arg208Gly	missense	Exon 7 of 12	NP_001373606.1
	ACAT1	NM_001386681.1		c.352C>G	p.Arg118Gly	missense	Exon 7 of 12	NP_001373610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.622C>G	p.Arg208Gly	missense	Exon 7 of 12	ENSP00000265838.4
	ACAT1	ENST00000531813.5	TSL:1	n.*95C>G		non_coding_transcript_exon	Exon 6 of 8	ENSP00000435965.1
	ACAT1	ENST00000531813.5	TSL:1	n.*95C>G		3_prime_UTR	Exon 6 of 8	ENSP00000435965.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Uncertain:1

Dec 05, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glycine at codon 208 of the ACAT1 protein (p.Arg208Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in an individual with clinical features of beta-ketothiolase deficiency (Invitae). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Arg208Gln and p.Arg208Gly) in affected individuals suggests that this may be a clinically significant residue (PMID: 17236799, Invitae). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		0.93	P
Vest4		0.95
MutPred		0.94		Loss of helix (P = 0.0237)
MVP		0.98
MPC		0.65
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.93
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs532190594; hg19: chr11-108010834;