Variant 14-73592321-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152331.4(ACOT4):c.362G>A(p.Cys121Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000055 ( 0 hom. )

Consequence

ACOT4
NM_152331.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.531

Variant links:

Genes affected

ACOT4 (HGNC:19748): (acyl-CoA thioesterase 4) Enables acyl-CoA hydrolase activity and succinyl-CoA hydrolase activity. Involved in carboxylic acid metabolic process; saturated monocarboxylic acid metabolic process; and succinyl-CoA metabolic process. Located in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACOT4 links:

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

HEATR4 links:

ENSG00000288797 (HGNC:):

ENSG00000288797 links:

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ACMG classification

Classification made for transcript

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=0.17112911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT4	NM_152331.4 link	c.362G>A	p.Cys121Tyr	missense_variant	Exon 1 of 3	ENST00000326303.5	NP_689544.3	Q8N9L9
HEATR4	XM_047431370.1 link	c.-73+41340C>T		intron_variant	Intron 1 of 16		XP_047287326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACOT4	ENST00000326303.5 link	c.362G>A	p.Cys121Tyr	missense_variant	Exon 1 of 3	1	NM_152331.4	ENSP00000323071.4	Q8N9L9
ENSG00000288797	ENST00000686335.1 link	n.183G>A		non_coding_transcript_exon_variant	Exon 1 of 2
ENSG00000258603	ENST00000664243.1 link	n.63-34349C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000340

AC:

AN:

235592

Hom.:

AF XY:

0.0000311

AC XY:

AN XY:

128806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1456496

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724378

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000181

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:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000498

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.362G>A (p.C121Y) alteration is located in exon 1 (coding exon 1) of the ACOT4 gene. This alteration results from a G to A substitution at nucleotide position 362, causing the cysteine (C) at amino acid position 121 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

0.32

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.092

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.053

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.78

Vest4

0.16

MutPred

0.62

Gain of phosphorylation at C121 (P = 0.0317);

MVP

0.51

MPC

0.86

ClinPred

0.63

GERP RS

0.52

Varity_R

0.87

gMVP

0.86

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