rs120074147

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000019.4(ACAT1):c.997G>C(p.Ala333Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000191 in 1,569,836 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACAT1
NM_000019.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.46

Publications

7 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACAT1 links:

ENSG00000285696 (HGNC:):

ENSG00000285696 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 11-108144039-G-C is Pathogenic according to our data. Variant chr11-108144039-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000019.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACAT1	NM_000019.4	MANE Select	c.997G>C	p.Ala333Pro	missense	Exon 10 of 12	NP_000010.1	P24752-1
ACAT1	NM_001386677.1		c.997G>C	p.Ala333Pro	missense	Exon 10 of 12	NP_001373606.1	A0A5F9ZHL1
ACAT1	NM_001386681.1		c.727G>C	p.Ala243Pro	missense	Exon 10 of 12	NP_001373610.1	A0A5F9ZHJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.997G>C	p.Ala333Pro	missense	Exon 10 of 12	ENSP00000265838.4	P24752-1
ACAT1	ENST00000907956.1		c.997G>C	p.Ala333Pro	missense	Exon 10 of 12	ENSP00000578015.1
ACAT1	ENST00000672354.1		c.997G>C	p.Ala333Pro	missense	Exon 10 of 12	ENSP00000500490.1	A0A5F9ZHL1

Frequencies

GnomAD3 genomes

AF:

0.00000699

AC:

AN:

143102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000211

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1426734

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32098

American (AMR)

AF:

0.00

AC:

AN:

43572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24718

East Asian (EAS)

AF:

0.0000540

AC:

AN:

37038

South Asian (SAS)

AF:

0.00

AC:

AN:

85884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089600

Other (OTH)

AF:

0.00

AC:

AN:

57832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

AF:

0.00000699

AC:

AN:

143102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69068

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37990

American (AMR)

AF:

0.00

AC:

AN:

13806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.000211

AC:

AN:

4730

South Asian (SAS)

AF:

0.00

AC:

AN:

4488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66766

Other (OTH)

AF:

0.00

AC:

AN:

1930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of acetyl-CoA acetyltransferase (6)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.1

PhyloP100

6.5

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.79

Vest4

0.85

MutPred

0.92

Loss of helix (P = 0.0626)

MVP

0.95

MPC

0.28

ClinPred

0.95

GERP RS

5.5

Varity_R

0.97

gMVP

0.96

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over