Genetic Variant NM_000019.4:c.622C>G (chr11-108140107-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000019.4(ACAT1):c.622C>G(p.Arg208Gly) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ACAT1
NM_000019.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

Publications

16 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-108140108-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198381.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

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.622C>G	p.Arg208Gly	missense	Exon 7 of 12	NP_000010.1	P24752-1
ACAT1	NM_001386677.1		c.622C>G	p.Arg208Gly	missense	Exon 7 of 12	NP_001373606.1	A0A5F9ZHL1
ACAT1	NM_001386681.1		c.352C>G	p.Arg118Gly	missense	Exon 7 of 12	NP_001373610.1	A0A5F9ZHJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.622C>G	p.Arg208Gly	missense	Exon 7 of 12	ENSP00000265838.4	P24752-1
ACAT1	ENST00000531813.5	TSL:1	n.*95C>G		non_coding_transcript_exon	Exon 6 of 8	ENSP00000435965.1	E9PRQ6
ACAT1	ENST00000531813.5	TSL:1	n.*95C>G		3_prime_UTR	Exon 6 of 8	ENSP00000435965.1	E9PRQ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of acetyl-CoA acetyltransferase (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PhyloP100

1.8

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.011

Polyphen

0.93

Vest4

0.95

MutPred

0.94

Loss of helix (P = 0.0237)

MVP

0.98

MPC

0.65

ClinPred

1.0

GERP RS

4.1

Varity_R

0.93

gMVP

0.93

Mutation Taster

=21/79

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over