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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The ENST00000265838.9(ACAT1):c.1A>C(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 0.00000572 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: 0.0000057 ( 0 hom. )

Consequence

ACAT1
ENST00000265838.9 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in ENST00000265838.9 (ACAT1) was described as [Pathogenic] in ClinVar as 666461

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108121607-A-C is Pathogenic according to our data. Variant chr11-108121607-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2867418.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAT1	NM_000019.4 linkuse as main transcript	c.1A>C	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 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/12	1	NM_000019.4	ENSP00000265838	P1	P24752-1
	ENST00000525548.1 linkuse as main transcript	n.78T>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000572

AC:

AN:

1398408

Hom.:

Cov.:

AF XY:

0.00000580

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000741

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change affects the initiator methionine of the ACAT1 mRNA. The next in-frame methionine is located at codon 91. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 8103405, 12754704). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects ACAT1 function (PMID: 8103405, 12754704). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.36

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-0.19

N;N

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;.

Vest4

0.76

MutPred

1.0

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.80

ClinPred

0.43

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.64

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over