Variant 14-73592167-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152331.4(ACOT4):c.208G>T(p.Gly70Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACOT4
NM_152331.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.01

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT4	NM_152331.4 link	c.208G>T	p.Gly70Cys	missense_variant	Exon 1 of 3	ENST00000326303.5	NP_689544.3	Q8N9L9
HEATR4	XM_047431370.1 link	c.-73+41494C>A		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.208G>T	p.Gly70Cys	missense_variant	Exon 1 of 3	1	NM_152331.4	ENSP00000323071.4	Q8N9L9
ENSG00000288797	ENST00000686335.1 link	n.29G>T		non_coding_transcript_exon_variant	Exon 1 of 2
ENSG00000258603	ENST00000664243.1 link	n.63-34195C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450724

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721286

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:

0.0000191

Gnomad4 NFE exome

AF:

0.00

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

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208G>T (p.G70C) alteration is located in exon 1 (coding exon 1) of the ACOT4 gene. This alteration results from a G to T substitution at nucleotide position 208, causing the glycine (G) at amino acid position 70 to be replaced by a cysteine (C). 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

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.79

MutPred

0.82

Gain of catalytic residue at A73 (P = 0.0025);

MVP

0.95

MPC

0.95

ClinPred

1.0

GERP RS

4.9

Varity_R

0.98

gMVP

0.89

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