14-73569779-G-A

Variant names:

• chr14-73569779-G-A
• rs1175609687
• NM_006821.6:c.539G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006821.6(ACOT2):​c.539G>A​(p.Arg180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACOT2 NM_006821.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.47

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]

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

ENSG00000258603 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08266476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT2	NM_006821.6	c.539G>A	p.Arg180Gln	missense_variant	Exon 1 of 3	ENST00000238651.10	NP_006812.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOT2	ENST00000238651.10	c.539G>A	p.Arg180Gln	missense_variant	Exon 1 of 3	1	NM_006821.6	ENSP00000238651.5
ACOT2	ENST00000613168.1	c.479G>A	p.Arg160Gln	missense_variant	Exon 1 of 3	1		ENSP00000477685.1
ACOT2	ENST00000538782.2	n.96+383G>A		intron_variant	Intron 2 of 3	2		ENSP00000440961.2
ENSG00000258603	ENST00000664243.1	n.63-11807C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000438 AC: 1 AN: 228478 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000574

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453814 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723066

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539G>A (p.R180Q) alteration is located in exon 1 (coding exon 1) of the ACOT2 gene. This alteration results from a G to A substitution at nucleotide position 539, causing the arginine (R) at amino acid position 180 to be replaced by a glutamine (Q). 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	Benign	0.087
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.0092	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.62	N;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;.;.
REVEL	Benign	0.028
Sift	Benign	0.41	T;.;.
Sift4G	Benign	0.53	T;T;T
Polyphen		0.23	B;.;.
Vest4		0.089
MutPred		0.53		Loss of sheet (P = 0.0315);.;.;
MVP		0.36
ClinPred		0.051	T
GERP RS		-4.7
Varity_R		0.099
gMVP		0.48

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

Other links and lift over

dbSNP: rs1175609687; hg19: chr14-74036483; COSMIC: COSV53151781; COSMIC: COSV53151781;