14-73569697-G-C

Variant names:

• chr14-73569697-G-C
• rs1455494870
• NM_006821.6:c.457G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006821.6(ACOT2):​c.457G>C​(p.Val153Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACOT2 NM_006821.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.92

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025054365).
• BP6: Variant 14-73569697-G-C is Benign according to our data. Variant chr14-73569697-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3481398.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT2	NM_006821.6	c.457G>C	p.Val153Leu	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.457G>C	p.Val153Leu	missense_variant	Exon 1 of 3	1	NM_006821.6	ENSP00000238651.5
ACOT2	ENST00000613168.1	c.397G>C	p.Val133Leu	missense_variant	Exon 1 of 3	1		ENSP00000477685.1
ACOT2	ENST00000538782.2	n.96+301G>C		intron_variant	Intron 2 of 3	2		ENSP00000440961.2
ENSG00000258603	ENST00000664243.1	n.63-11725C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457308 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0040
DANN	Benign	0.41
DEOGEN2	Benign	0.0080	T;T;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.027	T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.26	N;.;.
REVEL	Benign	0.030
Sift	Benign	0.70	T;.;.
Sift4G	Benign	0.79	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.034
MutPred		0.48		Gain of ubiquitination at K150 (P = 0.0523);.;.;
MVP		0.25
ClinPred		0.083	T
GERP RS		-6.9
Varity_R		0.083
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1455494870; hg19: chr14-74036401;