Genetic Variant ACAT1:p.Met1? (chr11-108121608-T-C) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000019.4(ACAT1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,398,374 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: 0.0000050 ( 0 hom. )

Consequence

ACAT1
NM_000019.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.55

Publications

4 publications found

Variant links:

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

ACAT1 links:

ENSG00000255467 (HGNC:):

ENSG00000255467 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 37 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 108134253. Lost 0.211 part of the original CDS.

PS1

Another start lost variant in NM_000019.4 (ACAT1) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108121608-T-C is Pathogenic according to our data. Variant chr11-108121608-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 666461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACAT1	NM_000019.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 12	NP_000010.1	P24752-1
ACAT1	NM_001386677.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 12	NP_001373606.1	A0A5F9ZHL1
ACAT1	NM_001386678.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 9	NP_001373607.1	A0A5F9ZI66

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000501

AC:

AN:

1398374

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

689860

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31650

American (AMR)

AF:

0.00

AC:

AN:

35788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.00

AC:

AN:

35846

South Asian (SAS)

AF:

0.00

AC:

AN:

79268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00000649

AC:

AN:

1079230

Other (OTH)

AF:

0.00

AC:

AN:

57956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of acetyl-CoA acetyltransferase (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.12

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.23

PhyloP100

1.5

PROVEAN

Benign

-0.27

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.039

Vest4

0.67

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.0115)

MVP

0.95

ClinPred

0.78

GERP RS

3.4

PromoterAI

-0.50

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.78

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over