rs35629489

chr17-75948415-G-Achr17-75948415-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004035.7(ACOX1):c.1771C>T(p.Arg591Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00263 in 1,614,062 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0087 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (23 hom.)
• Consequence: ACOX1 NM_004035.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.62

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018170953).
• BP6: Variant 17-75948415-G-A is Benign according to our data. Variant chr17-75948415-G-A is described in ClinVar as [Benign]. Clinvar id is 259221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75948415-G-A is described in Lovd as [Benign]. Variant chr17-75948415-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00872 (1327/152208) while in subpopulation AFR AF= 0.0259 (1077/41526). AF 95% confidence interval is 0.0246. There are 18 homozygotes in gnomad4. There are 668 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1319 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACOX1	NM_004035.7	c.1771C>T	p.Arg591Cys	missense_variant	13/14	ENST00000293217.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACOX1	ENST00000293217.10	c.1771C>T	p.Arg591Cys	missense_variant	13/14	1	NM_004035.7	A1

Frequencies

GnomAD3 genomes AF: 0.00867 AC: 1319 AN: 152090 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00363 AC: 912 AN: 251450 Hom.: 9 AF XY: 0.00314 AC XY: 427 AN XY: 135902

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00200 AC: 2925 AN: 1461854 Hom.: 23 Cov.: 32 AF XY: 0.00204 AC XY: 1483 AN XY: 727226

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00872

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000959

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.00872 AC: 1327 AN: 152208 Hom.: 18 Cov.: 31 AF XY: 0.00898 AC XY: 668 AN XY: 74402

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.00622

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00259 Hom.: 6

Bravo AF: 0.00928

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00376 AC: 457

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acyl-CoA oxidase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

ACOX1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.067	T;T
Polyphen		0.27	B;P
Vest4		0.69
MVP		0.61
MPC		0.54
ClinPred		0.039	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35629489; hg19: chr17-73944496; COSMIC: COSV53135000; COSMIC: COSV53135000;