17-75953459-G-C

Variant names:

• chr17-75953459-G-C
• rs1135640
• NM_004035.7:c.936C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 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. 15/21 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:10
• Conservation: PhyloP100: 1.13
• Publications: 47 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004035.7
• 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 VariationId is 259223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 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.936C>G	p.Ile312Met	missense	Exon 7 of 14	NP_004026.2
	ACOX1	NM_007292.6		c.936C>G	p.Ile312Met	missense	Exon 7 of 14	NP_009223.2
	ACOX1	NM_001185039.2		c.822C>G	p.Ile274Met	missense	Exon 7 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.936C>G	p.Ile312Met	missense	Exon 7 of 14	ENSP00000293217.4	Q15067-2
	ACOX1	ENST00000301608.9	TSL:1	c.936C>G	p.Ile312Met	missense	Exon 7 of 14	ENSP00000301608.4	Q15067-1
	ACOX1	ENST00000949477.1		c.1134C>G	p.Ile378Met	missense	Exon 9 of 16	ENSP00000619536.1

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

GnomAD2 exomes AF: 0.653 AC: 164061 AN: 251322 AF XY: 0.655

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 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

African (AFR) AF: 0.202 AC: 6771 AN: 33470

American (AMR) AF: 0.708 AC: 31646 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 15813 AN: 26118

East Asian (EAS) AF: 0.752 AC: 29817 AN: 39668

South Asian (SAS) AF: 0.646 AC: 55664 AN: 86222

European-Finnish (FIN) AF: 0.758 AC: 40448 AN: 53378

Middle Eastern (MID) AF: 0.502 AC: 2890 AN: 5758

European-Non Finnish (NFE) AF: 0.660 AC: 734198 AN: 1111612

Other (OTH) AF: 0.633 AC: 38232 AN: 60358

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

African (AFR) AF: 0.221 AC: 9172 AN: 41478

American (AMR) AF: 0.664 AC: 10107 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2071 AN: 3458

East Asian (EAS) AF: 0.789 AC: 4079 AN: 5172

South Asian (SAS) AF: 0.657 AC: 3165 AN: 4818

European-Finnish (FIN) AF: 0.763 AC: 8075 AN: 10580

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44710 AN: 67970

Other (OTH) AF: 0.554 AC: 1171 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Acyl-CoA oxidase deficiency (5)
-	-	3	not provided (3)
-	-	1	Mitchell syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.13
Sift	Benign	0.26	T
Sift4G	Benign	0.19	T
Polyphen		0.0070	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
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: rs1135640; hg19: chr17-73949540; COSMIC: COSV53135078; COSMIC: COSV53135078;