Variant 11-108121607-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_SupportingPM2PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.01

Variant links:

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 links:

ENSG00000255467 (HGNC:):

ENSG00000255467 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 270 CDS bases. Genomic position: 108134252. Lost 0.210 part of the original CDS.

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 rank	MANE	Protein	UniProt
ACAT1	NM_000019.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENST00000265838.9	NP_000010.1	P24752-1A0A140VJX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAT1	ENST00000265838.9 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	1	NM_000019.4	ENSP00000265838.4		P24752-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000662

AC:

AN:

151062

Hom.:

AF XY:

0.00

AC XY:

AN XY:

80852

show subpopulations

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:

AN:

1398408

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

689876

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase

Pathogenic:4

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 05, 2019

Department of Pediatrics, Gifu University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.096

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over