rs120074145

Variant names:

• chr11-108134260-A-G
• rs120074145
• NM_000019.4:c.278A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001386679.1(ACAT1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ACAT1 NM_001386679.1 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.82
• Publications: 6 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 31 codons. Genomic position: 108135195. Lost 0.092 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108134260-A-G is Pathogenic according to our data. Variant chr11-108134260-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2843.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386679.1. 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_000019.4	MANE Select	c.278A>G	p.Asn93Ser	missense	Exon 4 of 12	NP_000010.1	P24752-1
	ACAT1	NM_001386679.1		c.1A>G	p.Met1?	start_lost	Exon 4 of 12	NP_001373608.1
	ACAT1	NM_001386677.1		c.278A>G	p.Asn93Ser	missense	Exon 4 of 12	NP_001373606.1	A0A5F9ZHL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.278A>G	p.Asn93Ser	missense	Exon 4 of 12	ENSP00000265838.4	P24752-1
	ACAT1	ENST00000299355.10	TSL:1	c.278A>G	p.Asn93Ser	missense	Exon 4 of 6	ENSP00000299355.6	P24752-2
	ACAT1	ENST00000531813.5	TSL:1	n.278A>G		non_coding_transcript_exon	Exon 4 of 8	ENSP00000435965.1	E9PRQ6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.016	D
Polyphen		0.23	B
Vest4		0.82
MutPred		0.91		Loss of catalytic residue at N93 (P = 0.0297)
MVP		0.91
MPC		0.17
ClinPred		0.94	D
GERP RS		5.7
PromoterAI		0.011	Neutral
Varity_R		0.56
gMVP		0.76
Mutation Taster		=51/49	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs120074145; hg19: chr11-108004987;