11-108144039-GCA-CCT

Variant names:

• chr11-108144039-GCA-CCT
• NM_000019.4:c.997_999delGCAinsCCT
• ACAT1 p.Ala333Pro

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_000019.4(ACAT1):​c.997_999delGCAinsCCT​(p.Ala333Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 27)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.46
• 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

ENSG00000285696 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_000019.4 (ACAT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	NM_000019.4	MANE Select	c.997_999delGCAinsCCT	p.Ala333Pro	missense	N/A	NP_000010.1	P24752-1
	ACAT1	NM_001386677.1		c.997_999delGCAinsCCT	p.Ala333Pro	missense	N/A	NP_001373606.1	A0A5F9ZHL1
	ACAT1	NM_001386681.1		c.727_729delGCAinsCCT	p.Ala243Pro	missense	N/A	NP_001373610.1	A0A5F9ZHJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.997_999delGCAinsCCT	p.Ala333Pro	missense	N/A	ENSP00000265838.4	P24752-1
	ACAT1	ENST00000907956.1		c.997_999delGCAinsCCT	p.Ala333Pro	missense	N/A	ENSP00000578015.1
	ACAT1	ENST00000672354.1		c.997_999delGCAinsCCT	p.Ala333Pro	missense	N/A	ENSP00000500490.1	A0A5F9ZHL1

Frequencies

GnomAD3 genomes Cov.: 27

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-108014766;