rs886047594

Variant names:

• chr11-108121621-G-C
• rs886047594
• NM_000019.4:c.15G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108121621-G-C
• chr11-108121621-G-T
• chr11-108121621-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000019.4(ACAT1):​c.15G>C​(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ACAT1 NM_000019.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.147
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-108121621-G-C is Benign according to our data. Variant chr11-108121621-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302197.
• BP7: Synonymous conserved (PhyloP=0.147 with no splicing effect.

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.15G>C	p.Ala5Ala	synonymous	Exon 1 of 12	NP_000010.1	P24752-1
	ACAT1	NM_001386677.1		c.15G>C	p.Ala5Ala	synonymous	Exon 1 of 12	NP_001373606.1	A0A5F9ZHL1
	ACAT1	NM_001386678.1		c.15G>C	p.Ala5Ala	synonymous	Exon 1 of 9	NP_001373607.1	A0A5F9ZI66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.15G>C	p.Ala5Ala	synonymous	Exon 1 of 12	ENSP00000265838.4	P24752-1
	ACAT1	ENST00000299355.10	TSL:1	c.15G>C	p.Ala5Ala	synonymous	Exon 1 of 6	ENSP00000299355.6	P24752-2
	ACAT1	ENST00000531813.5	TSL:1	n.15G>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000435965.1	E9PRQ6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398556 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689998

African (AFR) AF: 0.00 AC: 0 AN: 31676

American (AMR) AF: 0.00 AC: 0 AN: 35828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35884

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079486

Other (OTH) AF: 0.00 AC: 0 AN: 57976

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Deficiency of acetyl-CoA acetyltransferase (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.15
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886047594; hg19: chr11-107992348;