17-8096638-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021628.3(ALOXE3):c.2125G>A(p.Val709Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000813 in 1,230,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

ALOXE3 (HGNC:13743): (arachidonate lipoxygenase 3) This gene is a member of the lipoxygenase family, which are catabolized by arachidonic acid-derived compounds. The encoded enzyme is a hydroperoxide isomerase that synthesizes a unique type of epoxy alcohol (8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid) from 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This epoxy alcohol can activate the the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which is implicated in epidermal differentiation. Loss of function of the enzyme encoded by this gene results in ichthyosis, implicating the function of this gene in the differentiation of human skin. This gene is part of a cluster of lipoxygenase genes on 17p13.1. Mutations in this gene result in nonbullous congenital ichthyosiform erythroderma (NCIE). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18668011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.2125G>A	p.Val709Ile	missense_variant	16/16	ENST00000448843.7
ALOXE3	NM_001165960.1	c.2521G>A	p.Val841Ile	missense_variant	16/16
ALOXE3	NM_001369446.1	c.2122G>A	p.Val708Ile	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.2125G>A	p.Val709Ile	missense_variant	16/16	1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.2125G>A	p.Val709Ile	missense_variant	15/15	1		P1
ALOXE3	ENST00000318227.4	c.2125G>A	p.Val709Ile	missense_variant	16/16	2		P1
ALOXE3	ENST00000583808.1	n.362G>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000813 AC: 10 AN: 1230608 Hom.: 0 Cov.: 19 AF XY: 0.0000112 AC XY: 7 AN XY: 623264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000405

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000777

Gnomad4 OTH exome AF: 0.0000190

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.2125G>A (p.V709I) alteration is located in exon 16 (coding exon 15) of the ALOXE3 gene. This alteration results from a G to A substitution at nucleotide position 2125, causing the valine (V) at amino acid position 709 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	0.0038
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.93	.;P;.
Vest4		0.16
MutPred		0.48		.;Gain of glycosylation at S708 (P = 0.0929);.;
MVP		0.74
MPC		0.11
ClinPred		0.71	D
GERP RS		4.4
Varity_R		0.066
gMVP		0.52

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: rs967438626; hg19: chr17-7999956;