rs150832314

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

congenital bile acid synthesis defect 6
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACOX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 VariationId is 375691.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOX2	NM_003500.4 link	c.673C>T	p.Arg225Trp	missense_variant	Exon 6 of 15	ENST00000302819.10	NP_003491.1
ACOX2	XM_047449042.1 link	c.871C>T	p.Arg291Trp	missense_variant	Exon 6 of 15		XP_047304998.1
ACOX2	XM_005265505.2 link	c.673C>T	p.Arg225Trp	missense_variant	Exon 6 of 15		XP_005265562.1	Q99424
ACOX2	XM_006713340.4 link	c.379C>T	p.Arg127Trp	missense_variant	Exon 5 of 14		XP_006713403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOX2	ENST00000302819.10 link	c.673C>T	p.Arg225Trp	missense_variant	Exon 6 of 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

GnomAD2 exomes

AF:

0.000318

AC:

AN:

251358

AF XY:

0.000287

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111994

Other (OTH)

AF:

0.000298

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000217

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41566

American (AMR)

AF:

0.000915

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000268

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

Nov 15, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 11, 2023

Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing;in vitro

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). -

Dec 24, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

(source)

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

PhyloP100

4.7

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

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over