11-108121608-T-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B.

PVS1PS1_ModeratePM2PP5_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

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.55

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

beta-ketothiolase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, Ambry Genetics

ACAT1 links:

ENSG00000255467 (HGNC:):

ENSG00000255467 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 37 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 108134253. Lost 0.211 part of the original CDS.

PS1

Another start lost variant in NM_000019.4 (ACAT1) was described as [Pathogenic] in ClinVar as 2867418

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
ACAT1	NM_000019.4 link	c.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
ACAT1	ENST00000265838.9 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 12	1	NM_000019.4	ENSP00000265838.4		P24752-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1398374

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689860

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31650

American (AMR)

AF:

0.00

AC:

AN:

35788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.00

AC:

AN:

35846

South Asian (SAS)

AF:

0.00

AC:

AN:

79268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1079230

Other (OTH)

AF:

0.00

AC:

AN:

57956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.41

PhyloP100

1.5

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

GERP RS

3.4

PromoterAI

-0.50

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.84

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over