NM_004035.7:c.532G>A

Variant names:

• chr17-75957465-C-T
• rs118204091
• NM_004035.7:c.532G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_004035.7(ACOX1):​c.532G>A​(p.Gly178Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G178C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACOX1 NM_004035.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.56
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-75957465-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1500.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 17-75957465-C-T is Pathogenic according to our data. Variant chr17-75957465-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 235416.Status of the report is criteria_provided_single_submitter, 1 stars.

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.532G>A	p.Gly178Ser	missense	Exon 4 of 14	NP_004026.2
	ACOX1	NM_007292.6		c.532G>A	p.Gly178Ser	missense	Exon 4 of 14	NP_009223.2
	ACOX1	NM_001185039.2		c.418G>A	p.Gly140Ser	missense	Exon 4 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.532G>A	p.Gly178Ser	missense	Exon 4 of 14	ENSP00000293217.4
	ACOX1	ENST00000301608.9	TSL:1	c.532G>A	p.Gly178Ser	missense	Exon 4 of 14	ENSP00000301608.4
	ACOX1	ENST00000572047.5	TSL:2	n.*490G>A		non_coding_transcript_exon	Exon 4 of 14	ENSP00000459936.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.80		Gain of glycosylation at G178 (P = 0.0036)
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

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: rs118204091; hg19: chr17-73953546; COSMIC: COSV107353320; COSMIC: COSV107353320;