11-108121598-T-A

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.-9T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,548,816 control chromosomes in the GnomAD database, including 83,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6932 hom., cov: 34)
  • Exomes 𝑓: 0.32 (76308 hom.)
• Consequence: ACAT1 NM_000019.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.31

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=-0.76).
• BP6: Variant 11-108121598-T-A is Benign according to our data. Variant chr11-108121598-T-A is described in ClinVar as [Benign]. Clinvar id is 92294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108121598-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT1	ENST00000265838.9	c.-9T>A		5_prime_UTR_variant	1/12	1	NM_000019.4	P1
	ENST00000525548.1	n.87A>T		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41578 AN: 152116 Hom.: 6932 Cov.: 34

Gnomad AFR AF: 0.0929

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.322

GnomAD3 exomes AF: 0.361 AC: 54490 AN: 150782 Hom.: 10593 AF XY: 0.368 AC XY: 29661 AN XY: 80608

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.334

Gnomad SAS exome AF: 0.478

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.323 AC: 451699 AN: 1396582 Hom.: 76308 Cov.: 36 AF XY: 0.329 AC XY: 226982 AN XY: 688990

Gnomad4 AFR exome AF: 0.0827

Gnomad4 AMR exome AF: 0.461

Gnomad4 ASJ exome AF: 0.370

Gnomad4 EAS exome AF: 0.341

Gnomad4 SAS exome AF: 0.481

Gnomad4 FIN exome AF: 0.312

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.273 AC: 41580 AN: 152234 Hom.: 6932 Cov.: 34 AF XY: 0.282 AC XY: 20959 AN XY: 74422

Gnomad4 AFR AF: 0.0926

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.327

Alfa AF: 0.314 Hom.: 2527

Bravo AF: 0.269

Asia WGS AF: 0.437 AC: 1517 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -

Deficiency of acetyl-CoA acetyltransferase Benign:3

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 13, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -

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	-0.76
Cadd	Benign	1.0
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3741055; hg19: chr11-107992325; COSMIC: COSV54920325; COSMIC: COSV54920325;