11-108121607-A-G

Position:

• chr11-108121607-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000019.4(ACAT1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,398,408 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: ACAT1 NM_000019.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.01

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108121607-A-G is Pathogenic according to our data. Variant chr11-108121607-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 666460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAT1	NM_000019.4	c.1A>G	p.Met1?	start_lost	1/12	ENST00000265838.9	NP_000010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAT1	ENST00000265838.9	c.1A>G	p.Met1?	start_lost	1/12	1	NM_000019.4	ENSP00000265838	P1
	ENST00000525548.1	n.78T>C		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000662 AC: 1 AN: 151062 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80852

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.00000930 AC: 13 AN: 1398408 Hom.: 0 Cov.: 38 AF XY: 0.0000116 AC XY: 8 AN XY: 689876

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: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The initiator codon variant p.M1V in ACAT1 (NM_000019.4) has been previously reported in individuals affected with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency (Abdelkreem et al, 2019; Nguyen et al, 2017). The variant is reported to have reduced translational efficiency (11%) (Fukao, Matsuo, et al, 2003). The p.M1V variant is has a gnomAD frequency of 0.0006620 %. The p.M1V variant is a loss of function variant in the gene ACAT1, which is intolerant of Loss of Function variants. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The nucleotide change in ACAT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.The observed variant has also been detected in the spouse in heterozygous state. -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Gifu University	May 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects ACAT1 function (PMID: 12754704). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 666460). Disruption of the initiator codon has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 12754704, 28220263). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the ACAT1 mRNA. The next in-frame methionine is located at codon 91. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.096	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.20	N;N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0040	B;.
Vest4		0.77
MutPred		1.0		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.86
ClinPred		0.49	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1305448140; hg19: chr11-107992334;