chr11-108135240-C-T

Variant names:

• chr11-108135240-C-T
• rs120074148
• NM_000019.4:c.433C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_001386677.1(ACAT1):​c.433C>T​(p.Gln145*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAT1 NM_001386677.1 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.64
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-108135240-C-T is Pathogenic according to our data. Variant chr11-108135240-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1705360.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386677.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	NM_000019.4	MANE Select	c.433C>T	p.Gln145*	stop_gained splice_region	Exon 5 of 12	NP_000010.1
	ACAT1	NM_001386677.1		c.433C>T	p.Gln145*	stop_gained splice_region	Exon 5 of 12	NP_001373606.1
	ACAT1	NM_001386681.1		c.163C>T	p.Gln55*	stop_gained splice_region	Exon 5 of 12	NP_001373610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.433C>T	p.Gln145*	stop_gained splice_region	Exon 5 of 12	ENSP00000265838.4
	ACAT1	ENST00000299355.10	TSL:1	c.433C>T	p.Gln145*	stop_gained splice_region	Exon 5 of 6	ENSP00000299355.6
	ACAT1	ENST00000531813.5	TSL:1	n.334+924C>T		intron	N/A	ENSP00000435965.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.6
Vest4		0.96
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.080		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: rs120074148; hg19: chr11-108005967;