11-108121619-G-C

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.13G>C(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,550,150 control chromosomes in the GnomAD database, including 84,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7292 hom., cov: 34)
  • Exomes 𝑓: 0.33 (76906 hom.)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.168

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 (MetaRNN=8.325577E-4).
• BP6: Variant 11-108121619-G-C is Benign according to our data. Variant chr11-108121619-G-C is described in ClinVar as [Benign]. Clinvar id is 92295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108121619-G-C 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.13G>C	p.Ala5Pro	missense_variant	1/12	ENST00000265838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT1	ENST00000265838.9	c.13G>C	p.Ala5Pro	missense_variant	1/12	1	NM_000019.4	P1
	ENST00000525548.1	n.66C>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44163 AN: 152138 Hom.: 7292 Cov.: 34

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.335

GnomAD3 exomes AF: 0.366 AC: 55070 AN: 150668 Hom.: 10694 AF XY: 0.371 AC XY: 29973 AN XY: 80832

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.332

Gnomad SAS exome AF: 0.479

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.326 AC: 455226 AN: 1397894 Hom.: 76906 Cov.: 39 AF XY: 0.331 AC XY: 228601 AN XY: 689712

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.384

Gnomad4 EAS exome AF: 0.341

Gnomad4 SAS exome AF: 0.482

Gnomad4 FIN exome AF: 0.312

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.335

GnomAD4 genome AF: 0.290 AC: 44168 AN: 152256 Hom.: 7292 Cov.: 34 AF XY: 0.298 AC XY: 22153 AN XY: 74426

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.346

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.340

Alfa AF: 0.320 Hom.: 2606

Bravo AF: 0.289

TwinsUK AF: 0.317 AC: 1174

ALSPAC AF: 0.318 AC: 1224

ESP6500AA AF: 0.122 AC: 498

ESP6500EA AF: 0.254 AC: 2021

ExAC AF: 0.198 AC: 17379

Asia WGS AF: 0.443 AC: 1537 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not specified Benign:3

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

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.00083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.015	D;T
Sift4G	Benign	0.37	T;T
Polyphen		0.61	P;.
Vest4		0.22
MPC		0.25
ClinPred		0.0074	T
GERP RS		0.20
Varity_R		0.14
gMVP		0.75

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: rs3741056; hg19: chr11-107992346; COSMIC: COSV54919984; COSMIC: COSV54919984;