17-8106846-C-A

Variant names:

• chr17-8106846-C-A
• rs7215658
• NM_021628.3:c.1684+1622G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021628.3(ALOXE3):​c.1684+1622G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 151,668 control chromosomes in the GnomAD database, including 39,867 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39867 hom., cov: 32)
• Consequence: ALOXE3 NM_021628.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.534
• Publications: 6 publications found

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]

ALOXE3 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• self-healing collodion baby

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOXE3	NM_021628.3	c.1684+1622G>T		intron_variant	Intron 13 of 15	ENST00000448843.7	NP_067641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOXE3	ENST00000448843.7	c.1684+1622G>T		intron_variant	Intron 13 of 15	1	NM_021628.3	ENSP00000400581.2

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109298 AN: 151550 Hom.: 39841 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.726

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.721 AC: 109368 AN: 151668 Hom.: 39867 Cov.: 32 AF XY: 0.717 AC XY: 53165 AN XY: 74138

African (AFR) AF: 0.670 AC: 27647 AN: 41280

American (AMR) AF: 0.675 AC: 10298 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2551 AN: 3462

East Asian (EAS) AF: 0.423 AC: 2180 AN: 5152

South Asian (SAS) AF: 0.651 AC: 3139 AN: 4822

European-Finnish (FIN) AF: 0.770 AC: 8103 AN: 10524

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53070 AN: 67868

Other (OTH) AF: 0.718 AC: 1513 AN: 2108

Alfa AF: 0.754 Hom.: 193719

Bravo AF: 0.710

Asia WGS AF: 0.550 AC: 1916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.42
PhyloP100		0.53
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: rs7215658; hg19: chr17-8010164;