Genetic Variant ACOX2:p.Arg50Leu (chr3-58534958-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003500.4(ACOX2):c.149G>T(p.Arg50Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,846 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACOX2
NM_003500.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ACOX2	NM_003500.4 link	c.149G>T	p.Arg50Leu	missense_variant	Exon 2 of 15	ENST00000302819.10	NP_003491.1
ACOX2	XM_047449042.1 link	c.347G>T	p.Arg116Leu	missense_variant	Exon 2 of 15		XP_047304998.1
ACOX2	XM_005265505.2 link	c.149G>T	p.Arg50Leu	missense_variant	Exon 2 of 15		XP_005265562.1
ACOX2	XM_006713340.4 link	c.-16G>T		5_prime_UTR_variant	Exon 1 of 14		XP_006713403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOX2	ENST00000302819.10 link	c.149G>T	p.Arg50Leu	missense_variant	Exon 2 of 15	1	NM_003500.4	ENSP00000307697.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111976

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T;T

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.3

.;M;.

PhyloP100

5.4

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.050

T;D;.

Polyphen

1.0

.;D;.

Vest4

0.82

MutPred

0.60

Loss of MoRF binding (P = 0.0591);Loss of MoRF binding (P = 0.0591);Loss of MoRF binding (P = 0.0591);

MVP

0.76

MPC

0.79

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.89

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over