NM_152331.4:c.566C>T

Variant names:

• chr14-73593810-C-T
• rs77261428
• NM_152331.4:c.566C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152331.4(ACOT4):​c.566C>T​(p.Ala189Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000104 in 961,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: ACOT4 NM_152331.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.96

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]

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOT4	NM_152331.4	c.566C>T	p.Ala189Val	missense_variant	Exon 2 of 3	ENST00000326303.5	NP_689544.3
HEATR4	XM_047431370.1	c.-73+39851G>A		intron_variant	Intron 1 of 16		XP_047287326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOT4	ENST00000326303.5	c.566C>T	p.Ala189Val	missense_variant	Exon 2 of 3	1	NM_152331.4	ENSP00000323071.4
ENSG00000258603	ENST00000664243.1	n.63-35838G>A		intron_variant	Intron 1 of 1
ENSG00000288797	ENST00000686335.1	n.279-1239C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000475 AC: 1 AN: 210474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 113284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000104 AC: 1 AN: 961386 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 482854

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: 0.00000147

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ExAC AF: 0.0000649 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.61		Gain of catalytic residue at A184 (P = 9e-04);
MVP		0.70
MPC		0.91
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.84
gMVP		0.81

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: rs77261428; hg19: chr14-74060514;