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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001386681.1(ACAT1):c.-199+4315dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00872 in 251,970 control chromosomes in the GnomAD database, including 9 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0093 ( 9 hom., cov: 0)

Exomes 𝑓: 0.0080 ( 0 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.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00929 (1320/142116) while in subpopulation NFE AF = 0.0154 (993/64678). AF 95% confidence interval is 0.0146. There are 9 homozygotes in GnomAd4. There are 578 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

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+4315dupA		intron	N/A	NP_001373610.1	A0A5F9ZHJ0
	ACAT1	NM_001386682.1		c.-416+4315dupA		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+4298_-199+4299insA		intron	N/A	ENSP00000500444.1	A0A5F9ZHJ0
	ENSG00000255467	ENST00000525548.1	TSL:3	n.389+95_389+96insT		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00931

AC:

1322

AN:

142050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00721

Gnomad ASJ

AF:

0.0129

Gnomad EAS

AF:

0.000412

Gnomad SAS

AF:

0.00221

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.0103

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.00729

GnomAD4 exome

AF:

0.00799

AC:

878

AN:

109854

Hom.:

AF XY:

0.00759

AC XY:

447

AN XY:

58860

show subpopulations

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

African (AFR)

AF:

0.00634

AC:

AN:

1734

American (AMR)

AF:

0.00675

AC:

AN:

4744

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

AN:

2246

East Asian (EAS)

AF:

0.000792

AC:

AN:

3788

South Asian (SAS)

AF:

0.00245

AC:

AN:

20822

European-Finnish (FIN)

AF:

0.00440

AC:

AN:

6368

Middle Eastern (MID)

AF:

0.00552

AC:

AN:

362

European-Non Finnish (NFE)

AF:

0.0108

AC:

692

AN:

64176

Other (OTH)

AF:

0.00552

AC:

AN:

5614

⚠️ 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: 0.329

Heterozygous variant carriers

123

185

246

308

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:

0.00929

AC:

1320

AN:

142116

Hom.:

Cov.:

AF XY:

0.00841

AC XY:

578

AN XY:

68694

show subpopulations

African (AFR)

AF:

0.00266

AC:

103

AN:

38690

American (AMR)

AF:

0.00721

AC:

103

AN:

14288

Ashkenazi Jewish (ASJ)

AF:

0.0129

AC:

AN:

3338

East Asian (EAS)

AF:

0.000414

AC:

AN:

4836

South Asian (SAS)

AF:

0.00200

AC:

AN:

4502

European-Finnish (FIN)

AF:

0.00574

AC:

AN:

8712

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0154

AC:

993

AN:

64678

Other (OTH)

AF:

0.00722

AC:

AN:

1938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00632

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-CAAAAAAA

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