17-75978627-C-G

Variant names:

• chr17-75978627-C-G
• rs777937235
• NM_004035.7:c.176G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004035.7(ACOX1):​c.176G>C​(p.Arg59Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACOX1 NM_004035.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 17-75978627-C-G is Pathogenic according to our data. Variant chr17-75978627-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216884.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004035.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOX1	NM_004035.7	MANE Select	c.176G>C	p.Arg59Pro	missense	Exon 2 of 14	NP_004026.2
	ACOX1	NM_007292.6		c.176G>C	p.Arg59Pro	missense	Exon 2 of 14	NP_009223.2
	ACOX1	NM_001185039.2		c.62G>C	p.Arg21Pro	missense	Exon 2 of 14	NP_001171968.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOX1	ENST00000293217.10	TSL:1 MANE Select	c.176G>C	p.Arg59Pro	missense	Exon 2 of 14	ENSP00000293217.4
	ACOX1	ENST00000301608.9	TSL:1	c.176G>C	p.Arg59Pro	missense	Exon 2 of 14	ENSP00000301608.4
	ACOX1	ENST00000588176.5	TSL:4	c.176G>C	p.Arg59Pro	missense	Exon 2 of 4	ENSP00000466210.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251494 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acyl-CoA oxidase deficiency Pathogenic:1 Uncertain:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 ACOX1 protein function. ClinVar contains an entry for this variant (Variation ID: 216884). This missense change has been observed in individual(s) with peroxisomal acyl-CoA oxidase deficiency (PMID: 25326637). This variant is present in population databases (rs777937235, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 59 of the ACOX1 protein (p.Arg59Pro).

Feb 18, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Mar 27, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACOX1 c.176G>C (p.Arg59Pro) results in a non-conservative amino acid change located in the Acyl-coenzyme A oxidase, N-terminal (IPR029320) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251494 control chromosomes. c.176G>C has been reported in the literature in individuals affected with Pseudoneonatal Adrenoleukodystrophy (Lee_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25326637). ClinVar contains an entry for this variant (Variation ID: 216884). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.040	D
Sift4G	Benign	0.19	T
Polyphen		0.68	P
Vest4		0.88
MutPred		0.64		Loss of MoRF binding (P = 0.0037)
MVP		0.64
MPC		1.9
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.011	Neutral
Varity_R		0.85
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs777937235; hg19: chr17-73974708;