Genetic Variant ACOT2:p.Leu143Pro (chr14-73569668-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006821.6(ACOT2):c.428T>C(p.Leu143Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,608,196 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ACOT2
NM_006821.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28

Variant links:

Genes affected

ACOT2 (HGNC:18431): (acyl-CoA thioesterase 2) This gene encodes a member of the acyl-CoA thioesterase protein family, and is one of four acyl-CoA hydrolase genes located in a cluster on chromosome 14. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ACOT2 links:

HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

HEATR4 links:

ENSG00000258603 (HGNC:):

ENSG00000258603 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT2	NM_006821.6 link	c.428T>C	p.Leu143Pro	missense_variant	Exon 1 of 3	ENST00000238651.10	NP_006812.3	P49753-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACOT2	ENST00000238651.10 link	c.428T>C	p.Leu143Pro	missense_variant	Exon 1 of 3	1	NM_006821.6	ENSP00000238651.5	P49753-1
ACOT2	ENST00000613168.1 link	c.368T>C	p.Leu123Pro	missense_variant	Exon 1 of 3	1		ENSP00000477685.1	A0A087WT95
ACOT2	ENST00000538782.2 link	n.96+272T>C		intron_variant	Intron 2 of 3	2		ENSP00000440961.2	F6VI00
ENSG00000258603	ENST00000664243.1 link	n.63-11696A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000297

AC:

AN:

235384

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129386

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000507

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1455888

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724164

show subpopulations

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428T>C (p.L143P) alteration is located in exon 1 (coding exon 1) of the ACOT2 gene. This alteration results from a T to C substitution at nucleotide position 428, causing the leucine (L) at amino acid position 143 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.0065

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.3

M;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.2

D;.;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;.;.

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.93

P;.;.

Vest4

0.80

MVP

0.86

ClinPred

0.58

GERP RS

3.6

Varity_R

0.96

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over