rs120074142

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate

The NM_000019.4(ACAT1):​c.2T>A​(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 0.00000286 in 1,398,374 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: 0.0000029 ( 0 hom. )

Consequence

ACAT1
NM_000019.4 start_lost

Scores

6
4
6

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.55
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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 11-108121608-T-A is Pathogenic according to our data. Variant chr11-108121608-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACAT1NM_000019.4 linkc.2T>A 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
ACAT1ENST00000265838.9 linkc.2T>A p.Met1? start_lost Exon 1 of 12 1 NM_000019.4 ENSP00000265838.4 P24752-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000286
AC:
4
AN:
1398374
Hom.:
0
Cov.:
37
AF XY:
0.00000290
AC XY:
2
AN XY:
689860
show subpopulations
Gnomad4 AFR exome
AF:
0.0000316
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:
0.00000278
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Pathogenic:2
Jan 01, 1993
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 05, 2019
Department of Pediatrics, Gifu University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.42
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.41
D
PROVEAN
Benign
-0.27
N;N
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.076
B;.
Vest4
0.76
MutPred
1.0
Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);
MVP
0.95
ClinPred
0.80
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.84

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.

Other links and lift over

dbSNP: rs120074142; hg19: chr11-107992335; API