rs35629489

Variant names:

• chr17-75948415-G-A
• rs35629489
• NM_004035.7:c.1771C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75948415-G-A
• chr17-75948415-G-T

Variant summary

Our verdict is Benign. The variant received -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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591H) 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/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.62
• Publications: 11 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 -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/Likely_benign. ClinVar VariationId is 259221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD gene

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.1771C>T	p.Arg591Cys	missense	Exon 13 of 14	NP_004026.2
	ACOX1	NM_007292.6		c.1771C>T	p.Arg591Cys	missense	Exon 13 of 14	NP_009223.2
	ACOX1	NM_001185039.2		c.1657C>T	p.Arg553Cys	missense	Exon 13 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.1771C>T	p.Arg591Cys	missense	Exon 13 of 14	ENSP00000293217.4	Q15067-2
	ACOX1	ENST00000301608.9	TSL:1	c.1771C>T	p.Arg591Cys	missense	Exon 13 of 14	ENSP00000301608.4	Q15067-1
	ACOX1	ENST00000949477.1		c.1969C>T	p.Arg657Cys	missense	Exon 15 of 16	ENSP00000619536.1

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

GnomAD2 exomes AF: 0.00363 AC: 912 AN: 251450 AF XY: 0.00314

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 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

African (AFR) AF: 0.0270 AC: 904 AN: 33478

American (AMR) AF: 0.00344 AC: 154 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00872 AC: 228 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00285 AC: 246 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.000959 AC: 1066 AN: 1112000

Other (OTH) AF: 0.00419 AC: 253 AN: 60394

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

African (AFR) AF: 0.0259 AC: 1077 AN: 41526

American (AMR) AF: 0.00622 AC: 95 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68026

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00377 Hom.: 14

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Acyl-CoA oxidase deficiency (3)
-	-	3	not provided (3)
-	-	1	ACOX1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.6
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.067	T
Polyphen		0.27	B
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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

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