rs150832314

Positions:

chr3-58531723-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_003500.4(ACOX2):c.673C>T(p.Arg225Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,614,176 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ACOX2
NM_003500.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 4.68

Variant links:

Genes affected

ACOX2 (HGNC:120): (acyl-CoA oxidase 2) The product of this gene belongs to the acyl-CoA oxidase family. It encodes the branched-chain acyl-CoA oxidase which is involved in the degradation of long branched fatty acids and bile acid intermediates in peroxisomes. Deficiency of this enzyme results in the accumulation of branched fatty acids and bile acid intermediates, and may lead to Zellweger syndrome, severe cognitive disability, and death in children. [provided by RefSeq, Mar 2009]

ACOX2 links:

ACOX2 (HGNC:):

ACOX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP5

Variant 3-58531723-G-A is Pathogenic according to our data. Variant chr3-58531723-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375691.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOX2	NM_003500.4 linkuse as main transcript	c.673C>T	p.Arg225Trp	missense_variant	6/15	ENST00000302819.10	NP_003491.1
ACOX2	XM_047449042.1 linkuse as main transcript	c.871C>T	p.Arg291Trp	missense_variant	6/15		XP_047304998.1
ACOX2	XM_005265505.2 linkuse as main transcript	c.673C>T	p.Arg225Trp	missense_variant	6/15		XP_005265562.1	Q99424
ACOX2	XM_006713340.4 linkuse as main transcript	c.379C>T	p.Arg127Trp	missense_variant	5/14		XP_006713403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACOX2	ENST00000302819.10 linkuse as main transcript	c.673C>T	p.Arg225Trp	missense_variant	6/15	1	NM_003500.4	ENSP00000307697.5		Q99424

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000318

AC:

AN:

251358

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000217

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital bile acid synthesis defect 6

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 24, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing;in vitro	Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III	Oct 11, 2023	According to "Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (oi:10.1038/gim.2015.30), the variant should be classified as "likely pathogenic", as literature supports strong evidence of pathogenicity (PS3), Moderate evidence of pathogenicity (PM2, PM3) and Supporting evidence of pathogenicity (PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2024	Variant summary: ACOX2 c.673C>T (p.Arg225Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251358 control chromosomes. c.673C>T has been reported in the literature in multiple individuals affected with Congenital Bile Acid Synthesis Defect 6 (Alonso-Pena_2022, Monte_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and suggests an impact on protein function (Monte_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27884763, 35395098). ClinVar contains an entry for this variant (Variation ID: 375691). Based on the evidence outlined above, the variant was classified as pathogenic. -

ACOX2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2023

The ACOX2 c.673C>T variant is predicted to result in the amino acid substitution p.Arg225Trp. This variant was reported in the homozygous and compound heterozygous states in individuals with congenital bile acid synthesis defect (Monte et al. 2017. PubMed ID: 27884763; Alonso-Peña et al. 2022. PubMed ID: 35395098). Functional assays indicate that the p.Arg225Trp variant reduces fatty acid beta-oxidation activity in vitro (Monte et al. 2017. PubMed ID: 27884763). This variant is reported in 0.16% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 225 of the ACOX2 protein (p.Arg225Trp). This variant is present in population databases (rs150832314, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ACOX2-related conditions (PMID: 27884763, 35395098). ClinVar contains an entry for this variant (Variation ID: 375691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACOX2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACOX2 function (PMID: 27884763). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

4.5

.;H

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.99

MVP

0.96

MPC

0.72

ClinPred

0.45

GERP RS

4.7

Varity_R

0.85

gMVP

0.95

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