rs8065946

Variant names:

• chr17-75949876-A-G
• rs8065946
• NM_004035.7:c.1320T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004035.7(ACOX1):​c.1320T>C​(p.Asp440Asp) 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
• Publications: 3 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: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Mitchell syndrome

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOX1	NM_004035.7	MANE Select	c.1320T>C	p.Asp440Asp	synonymous	Exon 10 of 14	NP_004026.2
	ACOX1	NM_007292.6		c.1320T>C	p.Asp440Asp	synonymous	Exon 10 of 14	NP_009223.2
	ACOX1	NM_001185039.2		c.1206T>C	p.Asp402Asp	synonymous	Exon 10 of 14	NP_001171968.1	Q15067-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOX1	ENST00000293217.10	TSL:1 MANE Select	c.1320T>C	p.Asp440Asp	synonymous	Exon 10 of 14	ENSP00000293217.4	Q15067-2
	ACOX1	ENST00000301608.9	TSL:1	c.1320T>C	p.Asp440Asp	synonymous	Exon 10 of 14	ENSP00000301608.4	Q15067-1
	ACOX1	ENST00000949477.1		c.1518T>C	p.Asp506Asp	synonymous	Exon 12 of 16	ENSP00000619536.1

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

GnomAD2 exomes AF: 0.0201 AC: 5060 AN: 251402 AF XY: 0.0162

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 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

African (AFR) AF: 0.219 AC: 7339 AN: 33476

American (AMR) AF: 0.0199 AC: 889 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 877 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00358 AC: 309 AN: 86258

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

Middle Eastern (MID) AF: 0.0349 AC: 201 AN: 5766

European-Non Finnish (NFE) AF: 0.00217 AC: 2411 AN: 1112010

Other (OTH) AF: 0.0224 AC: 1352 AN: 60396

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

African (AFR) AF: 0.209 AC: 8686 AN: 41510

American (AMR) AF: 0.0328 AC: 501 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 68024

Other (OTH) AF: 0.0525 AC: 111 AN: 2114

Alfa AF: 0.0276 Hom.: 487

Bravo AF: 0.0720

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Acyl-CoA oxidase deficiency (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.58
PhyloP100		-0.018
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs8065946; hg19: chr17-73945957;