NM_003500.4:c.1984_1986delGAG

Variant names:

• chr3-58505283-TCTC-T
• rs766533813
• NM_003500.4:c.1984_1986delGAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP3_Moderate

The NM_003500.4(ACOX2):​c.1984_1986delGAG​(p.Glu662del) variant causes a conservative inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: ACOX2 NM_003500.4 conservative_inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.359
• Publications: 0 publications found

Genes affected

ACOX2 (HGNC:120): (acyl-CoA oxidase 2) The product of this gene belongs to the acyl-CoA oxidase family. It encodes the branched-chain acyl-CoA oxidase which is involved in the degradation of long branched fatty acids and bile acid intermediates in peroxisomes. Deficiency of this enzyme results in the accumulation of branched fatty acids and bile acid intermediates, and may lead to Zellweger syndrome, severe cognitive disability, and death in children. [provided by RefSeq, Mar 2009]

ACOX2 Gene-Disease associations (from GenCC):

• congenital bile acid synthesis defect 6

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003500.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003500.4. 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
	ACOX2	NM_003500.4	MANE Select	c.1984_1986delGAG	p.Glu662del	conservative_inframe_deletion splice_region	Exon 15 of 15	NP_003491.1	Q99424

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOX2	ENST00000302819.10	TSL:1 MANE Select	c.1984_1986delGAG	p.Glu662del	conservative_inframe_deletion splice_region	Exon 15 of 15	ENSP00000307697.5	Q99424
	ACOX2	ENST00000900718.1		c.2056_2058delGAG	p.Glu686del	conservative_inframe_deletion splice_region	Exon 15 of 15	ENSP00000570777.1
	ACOX2	ENST00000900721.1		c.2008_2010delGAG	p.Glu670del	conservative_inframe_deletion splice_region	Exon 15 of 15	ENSP00000570780.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 249624 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1459786 Hom.: 0 AF XY: 0.0000275 AC XY: 20 AN XY: 726064

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.0000900 AC: 4 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85556

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111192

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: 0
DS_AL_spliceai		0.99		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766533813; hg19: chr3-58491010;