rs1135640

chr17-75953459-G-Cchr17-75953459-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.13

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=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 id is 259223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75953459-G-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ACOX1	NM_004035.7	c.936C>G	p.Ile312Met	missense_variant	7/14	ENST00000293217.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACOX1	ENST00000293217.10	c.936C>G	p.Ile312Met	missense_variant	7/14	1	NM_004035.7	A1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83314 AN: 151894 Hom.: 26185 Cov.: 31

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

GnomAD3 exomes AF: 0.653 AC: 164061 AN: 251322 Hom.: 55699 AF XY: 0.655 AC XY: 88993 AN XY: 135874

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 SAS exome AF: 0.644

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.: 55 AF XY: 0.654 AC XY: 475497 AN XY: 726972

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.708

Gnomad4 ASJ exome AF: 0.605

Gnomad4 EAS exome AF: 0.752

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.660

Gnomad4 OTH exome AF: 0.633

GnomAD4 genome AF: 0.548 AC: 83324 AN: 152012 Hom.: 26185 Cov.: 31 AF XY: 0.559 AC XY: 41545 AN XY: 74288

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.763

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.554

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acyl-CoA oxidase deficiency Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Mitchell syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Benign	0.92
Eigen	Benign	-0.066
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.0021	P;P;P;P;P
PrimateAI	Uncertain	0.56	T
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	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs1135640; hg19: chr17-73949540; COSMIC: COSV53135078; COSMIC: COSV53135078;