Genetic Variant ACAT1:c.-199+4315delA (chr11-108121200-CA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001386681.1(ACAT1):c.-199+4315delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 250,708 control chromosomes in the GnomAD database, including 1,800 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 1778 hom., cov: 0)

Exomes 𝑓: 0.16 ( 22 hom. )

Consequence

ACAT1
NM_001386681.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.114

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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

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+4315delA		intron	N/A	NP_001373610.1	A0A5F9ZHJ0
	ACAT1	NM_001386682.1		c.-416+4315delA		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+4299delA		intron	N/A	ENSP00000500444.1	A0A5F9ZHJ0
	ENSG00000255467	ENST00000525548.1	TSL:3	n.389+95delT		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

22839

AN:

141844

Hom.:

1777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.0481

Gnomad SAS

AF:

0.0830

Gnomad FIN

AF:

0.240

Gnomad MID

AF:

0.121

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.150

GnomAD4 exome

AF:

0.165

AC:

17925

AN:

108802

Hom.:

AF XY:

0.159

AC XY:

9291

AN XY:

58350

show subpopulations

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

African (AFR)

AF:

0.205

AC:

353

AN:

1718

American (AMR)

AF:

0.135

AC:

635

AN:

4700

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

377

AN:

2226

East Asian (EAS)

AF:

0.0688

AC:

258

AN:

3752

South Asian (SAS)

AF:

0.123

AC:

2532

AN:

20574

European-Finnish (FIN)

AF:

0.218

AC:

1379

AN:

6326

Middle Eastern (MID)

AF:

0.198

AC:

AN:

358

European-Non Finnish (NFE)

AF:

0.178

AC:

11343

AN:

63574

Other (OTH)

AF:

0.175

AC:

977

AN:

5574

⚠️ 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: 0.373

Heterozygous variant carriers

925

1851

2776

3702

4627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.161

AC:

22857

AN:

141906

Hom.:

1778

Cov.:

AF XY:

0.162

AC XY:

11077

AN XY:

68580

show subpopulations

African (AFR)

AF:

0.197

AC:

7607

AN:

38634

American (AMR)

AF:

0.116

AC:

1651

AN:

14264

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

454

AN:

3338

East Asian (EAS)

AF:

0.0482

AC:

233

AN:

4830

South Asian (SAS)

AF:

0.0838

AC:

377

AN:

4498

European-Finnish (FIN)

AF:

0.240

AC:

2087

AN:

8686

Middle Eastern (MID)

AF:

0.126

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.152

AC:

9831

AN:

64586

Other (OTH)

AF:

0.147

AC:

286

AN:

1940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

861

1722

2584

3445

4306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.0754

Hom.:

985

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.11

Splicing

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

Publications

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11-108121200-CAAAAAA-CAAAAA

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