rs1305448140

Variant names:

• chr11-108121607-A-C
• rs1305448140
• NM_000019.4:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108121607-A-C
• chr11-108121607-A-G
• chr11-108121607-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001386685.1(ACAT1):​c.-364A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,398,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: ACAT1 NM_001386685.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.01
• 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 11-108121607-A-C is Pathogenic according to our data. Variant chr11-108121607-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2867418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386685.1. 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.1A>C	p.Met1?	initiator_codon	Exon 1 of 12	NP_000010.1	P24752-1
	ACAT1	NM_001386685.1		c.-364A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_001373614.1	A0A5F9ZHJ0
	ACAT1	NM_001386686.1		c.-369A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_001373615.1	A0A5F9ZHJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 12	ENSP00000265838.4	P24752-1
	ACAT1	ENST00000299355.10	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000299355.6	P24752-2
	ACAT1	ENST00000531813.5	TSL:1	n.1A>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000435965.1	E9PRQ6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1398408 Hom.: 0 Cov.: 38 AF XY: 0.00000580 AC XY: 4 AN XY: 689876

African (AFR) AF: 0.00 AC: 0 AN: 31652

American (AMR) AF: 0.00 AC: 0 AN: 35786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35842

South Asian (SAS) AF: 0.00 AC: 0 AN: 79258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.00000741 AC: 8 AN: 1079222

Other (OTH) AF: 0.00 AC: 0 AN: 57956

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.36	T
PhyloP100		2.0
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.76
MutPred		1.0		Gain of helix (P = 0.0199)
MVP		0.80
ClinPred		0.43	T
GERP RS		2.3
PromoterAI		-0.58	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.64
Mutation Taster		=4/196	disease causing

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: rs1305448140; hg19: chr11-107992334;