11-108121200-CAAAAAA-CAAA

Variant names:

• chr11-108121200-CAAA-C
• rs10561331
• NM_001386681.1:c.-199+4313_-199+4315delAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001386681.1(ACAT1):​c.-199+4313_-199+4315delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 249,200 control chromosomes in the GnomAD database, including 21 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 0)
  • Exomes 𝑓: 0.20 (2 hom.)
• Consequence: ACAT1 NM_001386681.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.702
• Publications: 0 publications found

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

ENSG00000255467 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1453/142034) while in subpopulation AFR AF = 0.0288 (1113/38688). AF 95% confidence interval is 0.0274. There are 19 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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+4313_-199+4315delAAA		intron	N/A	NP_001373610.1	A0A5F9ZHJ0
	ACAT1	NM_001386682.1		c.-416+4313_-416+4315delAAA		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+4301delAAA		intron	N/A	ENSP00000500444.1	A0A5F9ZHJ0
	ENSG00000255467	ENST00000525548.1	TSL:3	n.389+93_389+95delTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1446 AN: 141968 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00617

Gnomad ASJ AF: 0.00240

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.000885

Gnomad FIN AF: 0.00864

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.0104

GnomAD4 exome AF: 0.201 AC: 21494 AN: 107166 Hom.: 2 AF XY: 0.203 AC XY: 11649 AN XY: 57374

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

African (AFR) AF: 0.219 AC: 375 AN: 1710

American (AMR) AF: 0.221 AC: 1017 AN: 4610

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 408 AN: 2208

East Asian (EAS) AF: 0.317 AC: 1172 AN: 3692

South Asian (SAS) AF: 0.234 AC: 4740 AN: 20224

European-Finnish (FIN) AF: 0.177 AC: 1097 AN: 6194

Middle Eastern (MID) AF: 0.201 AC: 70 AN: 348

European-Non Finnish (NFE) AF: 0.184 AC: 11565 AN: 62720

Other (OTH) AF: 0.192 AC: 1050 AN: 5460

⚠️ 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.

GnomAD4 genome AF: 0.0102 AC: 1453 AN: 142034 Hom.: 19 Cov.: 0 AF XY: 0.0104 AC XY: 717 AN XY: 68656

African (AFR) AF: 0.0288 AC: 1113 AN: 38688

American (AMR) AF: 0.00616 AC: 88 AN: 14276

Ashkenazi Jewish (ASJ) AF: 0.00240 AC: 8 AN: 3336

East Asian (EAS) AF: 0.00104 AC: 5 AN: 4830

South Asian (SAS) AF: 0.000888 AC: 4 AN: 4502

European-Finnish (FIN) AF: 0.00864 AC: 75 AN: 8676

Middle Eastern (MID) AF: 0.00370 AC: 1 AN: 270

European-Non Finnish (NFE) AF: 0.00212 AC: 137 AN: 64656

Other (OTH) AF: 0.0114 AC: 22 AN: 1936

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

Other links and lift over

dbSNP: rs10561331; hg19: chr11-107991927;