rs8065946

Positions:

• chr17-75949876-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004035.7(ACOX1):​c.1320T>C​(p.Asp440=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,130 control chromosomes in the GnomAD database, including 1,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (931 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (923 hom.)
• Consequence: ACOX1 NM_004035.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0180

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 17-75949876-A-G is Benign according to our data. Variant chr17-75949876-A-G is described in ClinVar as [Benign]. Clinvar id is 259220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.018 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOX1	NM_004035.7	c.1320T>C	p.Asp440=	synonymous_variant	10/14	ENST00000293217.10	NP_004026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACOX1	ENST00000293217.10	c.1320T>C	p.Asp440=	synonymous_variant	10/14	1	NM_004035.7	ENSP00000293217	A1
ACOX1	ENST00000301608.9	c.1320T>C	p.Asp440=	synonymous_variant	10/14	1		ENSP00000301608	P3
ACOX1	ENST00000572047.5	c.*1278T>C		3_prime_UTR_variant, NMD_transcript_variant	10/14	2		ENSP00000459936
ACOX1	ENST00000573078.5	c.*809T>C		3_prime_UTR_variant, NMD_transcript_variant	11/15	2		ENSP00000458325

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9605 AN: 152126 Hom.: 923 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0201 AC: 5060 AN: 251402 Hom.: 403 AF XY: 0.0162 AC XY: 2199 AN XY: 135864

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.00915 AC: 13380 AN: 1461886 Hom.: 923 Cov.: 32 AF XY: 0.00847 AC XY: 6160 AN XY: 727248

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.0336

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00358

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.0224

GnomAD4 genome AF: 0.0634 AC: 9651 AN: 152244 Hom.: 931 Cov.: 32 AF XY: 0.0613 AC XY: 4563 AN XY: 74444

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0211 Hom.: 267

Bravo AF: 0.0720

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00492

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	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs8065946; hg19: chr17-73945957;