rs200608977

Variant names:

• chr17-75949778-G-A
• rs200608977
• NM_004035.7:c.1418C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_004035.7(ACOX1):​c.1418C>T​(p.Thr473Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,614,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T473T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ACOX1 NM_004035.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:1
• Conservation: PhyloP100: 1.78
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010843426).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000315 (48/152226) while in subpopulation AMR AF = 0.00216 (33/15272). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1418C>T	p.Thr473Ile	missense	Exon 10 of 14	NP_004026.2
	ACOX1	NM_007292.6		c.1418C>T	p.Thr473Ile	missense	Exon 10 of 14	NP_009223.2
	ACOX1	NM_001185039.2		c.1304C>T	p.Thr435Ile	missense	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.1418C>T	p.Thr473Ile	missense	Exon 10 of 14	ENSP00000293217.4	Q15067-2
	ACOX1	ENST00000301608.9	TSL:1	c.1418C>T	p.Thr473Ile	missense	Exon 10 of 14	ENSP00000301608.4	Q15067-1
	ACOX1	ENST00000949477.1		c.1616C>T	p.Thr539Ile	missense	Exon 12 of 16	ENSP00000619536.1

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251472 AF XY: 0.000118

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000259 AC: 379 AN: 1461894 Hom.: 1 Cov.: 32 AF XY: 0.000250 AC XY: 182 AN XY: 727248

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000284 AC: 316 AN: 1112012

Other (OTH) AF: 0.000298 AC: 18 AN: 60396

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00216 AC: 33 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.000744

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	1	Acyl-CoA oxidase deficiency (3)
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.031
Sift	Uncertain	0.017	D
Sift4G	Benign	0.13	T
Polyphen		0.059	B
Vest4		0.22
MVP		0.60
MPC		0.13
ClinPred		0.052	T
GERP RS		2.4
PromoterAI		-0.0022	Neutral
Varity_R		0.028
gMVP		0.52
Mutation Taster		=92/8	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: rs200608977; hg19: chr17-73945859;