NM_000019.4:c.967A>G

Variant names:

• chr11-108144009-A-G
• rs1282394804
• NM_000019.4:c.967A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_000019.4(ACAT1):​c.967A>G​(p.Ile323Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,123,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I323T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 4.93
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108144010-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 666517.
• PP5: Variant 11-108144009-A-G is Pathogenic according to our data. Variant chr11-108144009-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532307.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26060575). . Strength limited to SUPPORTING due to the PP5.

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.967A>G	p.Ile323Val	missense	Exon 10 of 12	NP_000010.1	P24752-1
	ACAT1	NM_001386677.1		c.967A>G	p.Ile323Val	missense	Exon 10 of 12	NP_001373606.1	A0A5F9ZHL1
	ACAT1	NM_001386681.1		c.697A>G	p.Ile233Val	missense	Exon 10 of 12	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.967A>G	p.Ile323Val	missense	Exon 10 of 12	ENSP00000265838.4	P24752-1
	ACAT1	ENST00000907956.1		c.967A>G	p.Ile323Val	missense	Exon 10 of 12	ENSP00000578015.1
	ACAT1	ENST00000672354.1		c.967A>G	p.Ile323Val	missense	Exon 10 of 12	ENSP00000500490.1	A0A5F9ZHL1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.0000116 AC: 13 AN: 1123086 Hom.: 0 Cov.: 42 AF XY: 0.00000892 AC XY: 5 AN XY: 560710

African (AFR) AF: 0.00 AC: 0 AN: 24990

American (AMR) AF: 0.00 AC: 0 AN: 37234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16360

East Asian (EAS) AF: 0.00 AC: 0 AN: 16598

South Asian (SAS) AF: 0.00 AC: 0 AN: 81980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.0000150 AC: 13 AN: 867982

Other (OTH) AF: 0.00 AC: 0 AN: 41216

GnomAD4 genome Cov.: 26

Alfa AF: 0.000224 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	-	Deficiency of acetyl-CoA acetyltransferase (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.011
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.47	N
PhyloP100		4.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.25
Sift	Benign	0.45	T
Sift4G	Benign	0.47	T
Polyphen		0.053	B
Vest4		0.36
MutPred		0.28		Loss of catalytic residue at I323 (P = 0.0841)
MVP		0.71
MPC		0.13
ClinPred		0.76	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.72
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1282394804; hg19: chr11-108014736;