rs3027215

Variant names:

• chr17-8115188-C-T
• rs3027215
• NM_021628.3:c.435-131G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021628.3(ALOXE3):​c.435-131G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.099 in 1,285,510 control chromosomes in the GnomAD database, including 6,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1257 hom., cov: 32)
  • Exomes 𝑓: 0.096 (5707 hom.)
• Consequence: ALOXE3 NM_021628.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.511
• 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-8115188-C-T is Benign according to our data. Variant chr17-8115188-C-T is described in ClinVar as Benign. ClinVar VariationId is 1255270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021628.3. 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
	ALOXE3	NM_021628.3	MANE Select	c.435-131G>A		intron	N/A	NP_067641.2	Q9BYJ1-1
	ALOXE3	NM_001165960.1		c.831-131G>A		intron	N/A	NP_001159432.1	Q9BYJ1-2
	ALOXE3	NM_001369446.1		c.435-131G>A		intron	N/A	NP_001356375.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.435-131G>A		intron	N/A	ENSP00000400581.2	Q9BYJ1-1
	ALOXE3	ENST00000380149.6	TSL:1	c.435-131G>A		intron	N/A	ENSP00000369494.2	Q9BYJ1-1
	ALOXE3	ENST00000318227.4	TSL:2	c.435-131G>A		intron	N/A	ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18065 AN: 152170 Hom.: 1255 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.0964 AC: 109229 AN: 1133222 Hom.: 5707 AF XY: 0.0978 AC XY: 56051 AN XY: 572896

African (AFR) AF: 0.189 AC: 4999 AN: 26494

American (AMR) AF: 0.0654 AC: 2587 AN: 39572

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 3750 AN: 22874

East Asian (EAS) AF: 0.0434 AC: 1644 AN: 37898

South Asian (SAS) AF: 0.120 AC: 8993 AN: 75160

European-Finnish (FIN) AF: 0.0852 AC: 3451 AN: 40496

Middle Eastern (MID) AF: 0.157 AC: 793 AN: 5036

European-Non Finnish (NFE) AF: 0.0930 AC: 77729 AN: 836144

Other (OTH) AF: 0.107 AC: 5283 AN: 49548

GnomAD4 genome AF: 0.119 AC: 18078 AN: 152288 Hom.: 1257 Cov.: 32 AF XY: 0.118 AC XY: 8812 AN XY: 74468

African (AFR) AF: 0.186 AC: 7738 AN: 41548

American (AMR) AF: 0.0948 AC: 1451 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3472

East Asian (EAS) AF: 0.0423 AC: 219 AN: 5178

South Asian (SAS) AF: 0.120 AC: 580 AN: 4828

European-Finnish (FIN) AF: 0.0753 AC: 799 AN: 10610

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0921 AC: 6265 AN: 68034

Other (OTH) AF: 0.123 AC: 259 AN: 2110

Alfa AF: 0.101 Hom.: 2305

Bravo AF: 0.123

Asia WGS AF: 0.0960 AC: 331 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.46
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3027215;

hg19: chr17-8018506;

COSMIC: COSV107381807;