Genetic Variant NM_001365788.1:c.1033C>T (chr14-73619606-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001365788.1(ACOT6):c.1033C>T(p.His345Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACOT6
NM_001365788.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Variant links:

Genes affected

ACOT6 (HGNC:33159): (acyl-CoA thioesterase 6) Predicted to enable acyl-CoA hydrolase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACOT6 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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT6	NM_001365788.1 link	c.1033C>T	p.His345Tyr	missense_variant	Exon 3 of 3	ENST00000645972.2	NP_001352717.1
ACOT6	NM_001037162.1 link	c.391C>T	p.His131Tyr	missense_variant	Exon 2 of 2		NP_001032239.1	Q3I5F7-2
ACOT6	NM_001365789.1 link	c.391C>T	p.His131Tyr	missense_variant	Exon 4 of 4		NP_001352718.1
HEATR4	XM_047431370.1 link	c.-73+14055G>A		intron_variant	Intron 1 of 16		XP_047287326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOT6	ENST00000645972.2 link	c.1033C>T	p.His345Tyr	missense_variant	Exon 3 of 3		NM_001365788.1	ENSP00000496277.1		Q3I5F7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.391C>T (p.H131Y) alteration is located in exon 2 (coding exon 2) of the ACOT6 gene. This alteration results from a C to T substitution at nucleotide position 391, causing the histidine (H) at amino acid position 131 to be replaced by a tyrosine (Y). 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

0.092

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

.;.;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

3.0

.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Benign

0.17

Sift

Uncertain

0.024

D;.;D

Sift4G

Uncertain

0.034

D;.;D

Polyphen

0.82

.;.;P

Vest4

0.19

MutPred

0.77

Loss of disorder (P = 0.0516);.;Loss of disorder (P = 0.0516);

MVP

0.014

MPC

0.93

ClinPred

0.98

GERP RS

4.9

Varity_R

0.53

gMVP

0.54

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over