rs1135640

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_004035.7(ACOX1):c.936C>G(p.Ile312Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,613,296 control chromosomes in the GnomAD database, including 343,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 26185 hom., cov: 31)

Exomes 𝑓: 0.65 ( 317329 hom. )

Consequence

ACOX1
NM_004035.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.13

Publications

47 publications found

Variant links:

Genes affected

ACOX1 (HGNC:119): (acyl-CoA oxidase 1) The protein encoded by this gene is the first enzyme of the fatty acid beta-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs. It donates electrons directly to molecular oxygen, thereby producing hydrogen peroxide. Defects in this gene result in pseudoneonatal adrenoleukodystrophy, a disease that is characterized by accumulation of very long chain fatty acids. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACOX1 Gene-Disease associations (from GenCC):

peroxisomal acyl-CoA oxidase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics, Orphanet
Mitchell syndrome
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

ACOX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004035.7

BP4

Computational evidence support a benign effect (MetaRNN=1.0736948E-6).

BP6

Variant 17-75953459-G-C is Benign according to our data. Variant chr17-75953459-G-C is described in ClinVar as Benign. ClinVar VariationId is 259223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOX1	NM_004035.7 link	c.936C>G	p.Ile312Met	missense_variant	Exon 7 of 14	ENST00000293217.10	NP_004026.2	Q15067-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOX1	ENST00000293217.10 link	c.936C>G	p.Ile312Met	missense_variant	Exon 7 of 14	1	NM_004035.7	ENSP00000293217.4		Q15067-2

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83314

AN:

151894

Hom.:

26185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.677

Gnomad AMR

AF:

0.663

Gnomad ASJ

AF:

0.599

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.658

Gnomad FIN

AF:

0.763

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.559

GnomAD2 exomes

AF:

0.653

AC:

164061

AN:

251322

AF XY:

0.655

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.714

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.800

Gnomad FIN exome

AF:

0.766

Gnomad NFE exome

AF:

0.659

Gnomad OTH exome

AF:

0.644

GnomAD4 exome

AF:

0.654

AC:

955479

AN:

1461284

Hom.:

317329

Cov.:

AF XY:

0.654

AC XY:

475497

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.202

AC:

6771

AN:

33470

American (AMR)

AF:

0.708

AC:

31646

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.605

AC:

15813

AN:

26118

East Asian (EAS)

AF:

0.752

AC:

29817

AN:

39668

South Asian (SAS)

AF:

0.646

AC:

55664

AN:

86222

European-Finnish (FIN)

AF:

0.758

AC:

40448

AN:

53378

Middle Eastern (MID)

AF:

0.502

AC:

2890

AN:

5758

European-Non Finnish (NFE)

AF:

0.660

AC:

734198

AN:

1111612

Other (OTH)

AF:

0.633

AC:

38232

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

17965

35929

53894

71858

89823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18982

37964

56946

75928

94910

<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:

0.548

AC:

83324

AN:

152012

Hom.:

26185

Cov.:

AF XY:

0.559

AC XY:

41545

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.221

AC:

9172

AN:

41478

American (AMR)

AF:

0.664

AC:

10107

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

2071

AN:

3458

East Asian (EAS)

AF:

0.789

AC:

4079

AN:

5172

South Asian (SAS)

AF:

0.657

AC:

3165

AN:

4818

European-Finnish (FIN)

AF:

0.763

AC:

8075

AN:

10580

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.658

AC:

44710

AN:

67970

Other (OTH)

AF:

0.554

AC:

1171

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1608

3216

4823

6431

8039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.635

Hom.:

23657

Bravo

AF:

0.525

TwinsUK

AF:

0.649

AC:

2408

ALSPAC

AF:

0.658

AC:

2535

ESP6500AA

AF:

0.235

AC:

1034

ESP6500EA

AF:

0.649

AC:

5582

ExAC

AF:

0.642

AC:

77994

Asia WGS

AF:

0.665

AC:

2311

AN:

3478

EpiCase

AF:

0.644

EpiControl

AF:

0.638

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acyl-CoA oxidase deficiency

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitchell syndrome

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.066

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.7

L;L

PhyloP100

1.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.13

Sift

Benign

0.26

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.0070

B;B

Vest4

0.28

MPC

0.65

ClinPred

0.012

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.57

Mutation Taster

=100/0

polymorphism (auto)

(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