11-108121585-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000019.4(ACAT1):c.-22C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,549,518 control chromosomes in the GnomAD database, including 22,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1529 hom., cov: 34)
  • Exomes 𝑓: 0.17 (20601 hom.)
• Consequence: ACAT1 NM_000019.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-108121585-C-G is Benign according to our data. Variant chr11-108121585-C-G is described in ClinVar as [Benign]. Clinvar id is 302195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAT1	NM_000019.4	c.-22C>G		5_prime_UTR_variant	1/12	ENST00000265838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT1	ENST00000265838.9	c.-22C>G		5_prime_UTR_variant	1/12	1	NM_000019.4	P1
	ENST00000525548.1	n.100G>C		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20741 AN: 152196 Hom.: 1529 Cov.: 34

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.142 AC: 21347 AN: 150434 Hom.: 1755 AF XY: 0.147 AC XY: 11822 AN XY: 80322

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0191

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.168 AC: 235381 AN: 1397204 Hom.: 20601 Cov.: 30 AF XY: 0.169 AC XY: 116234 AN XY: 689214

Gnomad4 AFR exome AF: 0.0967

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0432

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.136 AC: 20738 AN: 152314 Hom.: 1529 Cov.: 34 AF XY: 0.134 AC XY: 10003 AN XY: 74472

Gnomad4 AFR AF: 0.0949

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0238

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.129

Alfa AF: 0.105 Hom.: 239

Bravo AF: 0.130

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.40
Dann	Benign	0.45

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: rs3741054; hg19: chr11-107992312; COSMIC: COSV54922494; COSMIC: COSV54922494;