17-8096639-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021628.3(ALOXE3):c.2124C>T(p.Ser708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,385,774 control chromosomes in the GnomAD database, including 128,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12756 hom., cov: 31)
  • Exomes 𝑓: 0.43 (115753 hom.)
• Consequence: ALOXE3 NM_021628.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.101

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-8096639-G-A is Benign according to our data. Variant chr17-8096639-G-A is described in ClinVar as [Benign]. Clinvar id is 261424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8096639-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.2124C>T	p.Ser708=	synonymous_variant	16/16	ENST00000448843.7
ALOXE3	NM_001165960.1	c.2520C>T	p.Ser840=	synonymous_variant	16/16
ALOXE3	NM_001369446.1	c.2121C>T	p.Ser707=	synonymous_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.2124C>T	p.Ser708=	synonymous_variant	16/16	1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.2124C>T	p.Ser708=	synonymous_variant	15/15	1		P1
ALOXE3	ENST00000318227.4	c.2124C>T	p.Ser708=	synonymous_variant	16/16	2		P1
ALOXE3	ENST00000583808.1	n.361C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60491 AN: 151812 Hom.: 12738 Cov.: 31

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.460 AC: 115596 AN: 251468 Hom.: 28178 AF XY: 0.452 AC XY: 61382 AN XY: 135904

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.663

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.637

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.427 AC: 526714 AN: 1233842 Hom.: 115753 Cov.: 19 AF XY: 0.424 AC XY: 265094 AN XY: 624766

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.649

Gnomad4 ASJ exome AF: 0.449

Gnomad4 EAS exome AF: 0.630

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.461

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.398 AC: 60544 AN: 151932 Hom.: 12756 Cov.: 31 AF XY: 0.405 AC XY: 30068 AN XY: 74228

Gnomad4 AFR AF: 0.279

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.418

Alfa AF: 0.414 Hom.: 26631

Bravo AF: 0.404

Asia WGS AF: 0.491 AC: 1707 AN: 3478

EpiCase AF: 0.414

EpiControl AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive congenital ichthyosis 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.28
Dann	Benign	0.54

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: rs3809881; hg19: chr17-7999957; COSMIC: COSV59074677;