2-110841385-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001142807.4(ACOXL):c.768A>G(p.Ile256Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,457,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I256V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ACOXL NM_001142807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

Genes affected

ACOXL (HGNC:25621): (acyl-CoA oxidase like) Predicted to enable acyl-CoA oxidase activity; fatty acid binding activity; and flavin adenine dinucleotide binding activity. Predicted to be involved in fatty acid beta-oxidation using acyl-CoA oxidase and lipid homeostasis. Predicted to be located in peroxisomal matrix. Predicted to be active in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACOXL	NM_001142807.4	c.768A>G	p.Ile256Met	missense_variant	10/18	ENST00000439055.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACOXL	ENST00000439055.6	c.768A>G	p.Ile256Met	missense_variant	10/18	2	NM_001142807.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248694 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1457676 Hom.: 0 Cov.: 29 AF XY: 0.00000965 AC XY: 7 AN XY: 725142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000902

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.768A>G (p.I256M) alteration is located in exon 10 (coding exon 9) of the ACOXL gene. This alteration results from a A to G substitution at nucleotide position 768, causing the isoleucine (I) at amino acid position 256 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;.
Eigen	Benign	0.059
Eigen_PC	Benign	-0.0014
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.1	M;M;M;.
MutationTaster	Benign	0.57	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;N;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.52
MutPred		0.66		Gain of catalytic residue at I256 (P = 0.0362);Gain of catalytic residue at I256 (P = 0.0362);Gain of catalytic residue at I256 (P = 0.0362);.;
MVP		0.74
MPC		0.72
ClinPred		0.83	D
GERP RS		2.7
Varity_R		0.70
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs777944015; hg19: chr2-111598962;