17-75945874-G-A

Variant names:

• chr17-75945874-G-A
• rs12430
• NM_004035.7:c.*874C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004035.7(ACOX1):​c.*874C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 151,808 control chromosomes in the GnomAD database, including 1,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1020 hom., cov: 32)
  • Exomes 𝑓: 0.15 (1 hom.)
• Consequence: ACOX1 NM_004035.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.150
• Publications: 13 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics, Orphanet
• Mitchell syndrome

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-75945874-G-A is Benign according to our data. Variant chr17-75945874-G-A is described in ClinVar as [Benign]. Clinvar id is 325356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACOX1	NM_004035.7	c.*874C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000293217.10	NP_004026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACOX1	ENST00000293217.10	c.*874C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_004035.7	ENSP00000293217.4
ACOX1	ENST00000301608.9	c.*874C>T		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000301608.4
ACOX1	ENST00000588968.5	c.387+2377C>T		intron_variant	Intron 3 of 3	5		ENSP00000468651.1
ACOX1	ENST00000587927.5	c.*41+833C>T		intron_variant	Intron 3 of 3	3		ENSP00000466921.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16776 AN: 151456 Hom.: 1016 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0758

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0901

GnomAD4 exome AF: 0.149 AC: 37 AN: 248 Hom.: 1 Cov.: 0 AF XY: 0.125 AC XY: 16 AN XY: 128

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.140 AC: 34 AN: 242

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.111 AC: 16787 AN: 151560 Hom.: 1020 Cov.: 32 AF XY: 0.110 AC XY: 8116 AN XY: 74034

African (AFR) AF: 0.141 AC: 5826 AN: 41322

American (AMR) AF: 0.0759 AC: 1154 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3470

East Asian (EAS) AF: 0.0782 AC: 404 AN: 5168

South Asian (SAS) AF: 0.119 AC: 571 AN: 4800

European-Finnish (FIN) AF: 0.117 AC: 1216 AN: 10356

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.103 AC: 6985 AN: 67928

Other (OTH) AF: 0.0911 AC: 192 AN: 2108

Alfa AF: 0.103 Hom.: 1413

Bravo AF: 0.110

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acyl-CoA oxidase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.36
PhyloP100		-0.15
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: rs12430; hg19: chr17-73941955;