dbSNP rs777937235: ACOX1:p.Arg59Leu (chr17-75978627-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_004035.7(ACOX1):c.176G>T(p.Arg59Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R59P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACOX1
NM_004035.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.73

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-75978627-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216884.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ACOX1	NM_004035.7 link	c.176G>T	p.Arg59Leu	missense_variant	Exon 2 of 14	ENST00000293217.10	NP_004026.2
ACOX1	NM_007292.6 link	c.176G>T	p.Arg59Leu	missense_variant	Exon 2 of 14		NP_009223.2
ACOX1	NM_001185039.2 link	c.62G>T	p.Arg21Leu	missense_variant	Exon 2 of 14		NP_001171968.1
ACOX1	XM_047436183.1 link	c.-72G>T		5_prime_UTR_variant	Exon 1 of 12		XP_047292139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOX1	ENST00000293217.10 link	c.176G>T	p.Arg59Leu	missense_variant	Exon 2 of 14	1	NM_004035.7	ENSP00000293217.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

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:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

.;T;.

Eigen

Benign

0.086

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

7.7

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

D;D;.

REVEL

Uncertain

0.43

Sift

Benign

0.11

T;T;.

Sift4G

Benign

0.59

T;T;.

Polyphen

0.013

B;B;.

Vest4

0.83

MutPred

0.56

Loss of MoRF binding (P = 0.0169);Loss of MoRF binding (P = 0.0169);Loss of MoRF binding (P = 0.0169);

MVP

0.49

MPC

0.85

ClinPred

0.99

GERP RS

4.5

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.93

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over