Variant 4-8375131-C-G 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_003501.3(ACOX3):c.1675G>C(p.Ala559Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ACOX3
NM_003501.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.94

Variant links:

Genes affected

ACOX3 (HGNC:121): (acyl-CoA oxidase 3, pristanoyl) Acyl-Coenzyme A oxidase 3 also know as pristanoyl -CoA oxidase (ACOX3)is involved in the desaturation of 2-methyl branched fatty acids in peroxisomes. Unlike the rat homolog, the human gene is expressed in very low amounts in liver such that its mRNA was undetectable by routine Northern-blot analysis or its product by immunoblotting or by enzyme activity measurements. However the human cDNA encoding a 700 amino acid protein with a peroxisomal targeting C-terminal tripeptide S-K-L was isolated and is thought to be expressed under special conditions such as specific developmental stages or in a tissue specific manner in tissues that have not yet been examined. [provided by RefSeq, Jul 2008]

ACOX3 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, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOX3	NM_003501.3 link	c.1675G>C	p.Ala559Pro	missense_variant	15/18	ENST00000356406.10	NP_003492.2	O15254-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACOX3	ENST00000356406.10 link	c.1675G>C	p.Ala559Pro	missense_variant	15/18	1	NM_003501.3	ENSP00000348775.4	O15254-1
ACOX3	ENST00000503233.5 link	c.1675G>C	p.Ala559Pro	missense_variant	15/18	1		ENSP00000421625.1	O15254-1
ACOX3	ENST00000413009.6 link	c.1675G>C	p.Ala559Pro	missense_variant	15/17	1		ENSP00000413994.2	O15254-2
ACOX3	ENST00000510365.5 link	n.1387G>C		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.1675G>C (p.A559P) alteration is located in exon 15 (coding exon 14) of the ACOX3 gene. This alteration results from a G to C substitution at nucleotide position 1675, causing the alanine (A) at amino acid position 559 to be replaced by a proline (P). 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

0.83

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Uncertain

-0.053

MutationAssessor

Pathogenic

3.1

M;M;M

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.80

Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);

MVP

0.71

MPC

0.56

ClinPred

1.0

GERP RS

4.3

Varity_R

0.88

gMVP

0.88

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