Genetic Variant ACAT1:c.-199+4312_-199+4315delAAAA (chr11-108121200-CAAAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001386681.1(ACAT1):c.-199+4312_-199+4315delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 249,552 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 0)

Exomes 𝑓: 0.024 ( 0 hom. )

Consequence

ACAT1
NM_001386681.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.702

Publications

0 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:

ENSG00000255467 (HGNC:):

ENSG00000255467 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the EAS (0.0399) population. However there is too low homozygotes in high coverage region: (expected more than 6, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386681.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	NM_001386681.1		c.-199+4312_-199+4315delAAAA		intron	N/A	NP_001373610.1	A0A5F9ZHJ0
	ACAT1	NM_001386682.1		c.-416+4312_-416+4315delAAAA		intron	N/A	NP_001373611.1	A0A5F9ZHJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000672284.1		c.-199+4299_-199+4302delAAAA		intron	N/A	ENSP00000500444.1	A0A5F9ZHJ0
	ENSG00000255467	ENST00000525548.1	TSL:3	n.389+92_389+95delTTTT		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000563

AC:

AN:

142032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000518

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000701

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000115

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000618

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0236

AC:

2539

AN:

107452

Hom.:

AF XY:

0.0244

AC XY:

1405

AN XY:

57524

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0309

AC:

AN:

1714

American (AMR)

AF:

0.0248

AC:

115

AN:

4636

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

AN:

2196

East Asian (EAS)

AF:

0.0456

AC:

167

AN:

3666

South Asian (SAS)

AF:

0.0263

AC:

533

AN:

20258

European-Finnish (FIN)

AF:

0.0204

AC:

127

AN:

6218

Middle Eastern (MID)

AF:

0.0169

AC:

AN:

354

European-Non Finnish (NFE)

AF:

0.0217

AC:

1364

AN:

62916

Other (OTH)

AF:

0.0222

AC:

122

AN:

5494

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.272

Heterozygous variant carriers

238

475

713

950

1188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000563

AC:

AN:

142100

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

68684

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000517

AC:

AN:

38682

American (AMR)

AF:

0.0000700

AC:

AN:

14286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3336

East Asian (EAS)

AF:

0.00

AC:

AN:

4836

South Asian (SAS)

AF:

0.00

AC:

AN:

4502

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

8694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000618

AC:

AN:

64690

Other (OTH)

AF:

0.00

AC:

AN:

1940

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0145482), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

985

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-108121200-CAAAAAA-CAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over