rs3027232

Variant names:

• chr17-8118747-G-A
• rs3027232
• ENST00000318227.4:c.-365C>T

Variant summary

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

The NM_001165960.1(ALOXE3):​c.32C>T​(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,537,118 control chromosomes in the GnomAD database, including 55,796 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6683 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49113 hom.)
• Consequence: ALOXE3 NM_001165960.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.194
• Publications: 24 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 (MetaRNN=3.040731E-4).
• BP6: Variant 17-8118747-G-A is Benign according to our data. Variant chr17-8118747-G-A is described in ClinVar as Benign. ClinVar VariationId is 1188973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165960.1. 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_001165960.1		c.32C>T	p.Pro11Leu	missense	Exon 1 of 16	NP_001159432.1	Q9BYJ1-2
	ALOXE3	NM_021628.3	MANE Select	c.-575C>T		upstream_gene	N/A	NP_067641.2	Q9BYJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	ENST00000318227.4	TSL:2	c.-365C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000314879.4	Q9BYJ1-1
	ALOXE3	ENST00000318227.4	TSL:2	c.-365C>T		5_prime_UTR	Exon 1 of 16	ENSP00000314879.4	Q9BYJ1-1
	ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.-575C>T		upstream_gene	N/A	ENSP00000400581.2	Q9BYJ1-1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43242 AN: 152068 Hom.: 6661 Cov.: 33

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.290

GnomAD2 exomes AF: 0.334 AC: 47376 AN: 141824 AF XY: 0.330

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.530

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.253 AC: 350482 AN: 1384932 Hom.: 49113 Cov.: 37 AF XY: 0.257 AC XY: 175891 AN XY: 683396

African (AFR) AF: 0.336 AC: 10600 AN: 31594

American (AMR) AF: 0.506 AC: 18064 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7533 AN: 25180

East Asian (EAS) AF: 0.517 AC: 18461 AN: 35734

South Asian (SAS) AF: 0.402 AC: 31833 AN: 79234

European-Finnish (FIN) AF: 0.210 AC: 7352 AN: 35004

Middle Eastern (MID) AF: 0.320 AC: 1824 AN: 5696

European-Non Finnish (NFE) AF: 0.221 AC: 238832 AN: 1078880

Other (OTH) AF: 0.276 AC: 15983 AN: 57912

GnomAD4 genome AF: 0.284 AC: 43287 AN: 152186 Hom.: 6683 Cov.: 33 AF XY: 0.290 AC XY: 21566 AN XY: 74406

African (AFR) AF: 0.319 AC: 13261 AN: 41518

American (AMR) AF: 0.409 AC: 6255 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1026 AN: 3470

East Asian (EAS) AF: 0.463 AC: 2390 AN: 5164

South Asian (SAS) AF: 0.415 AC: 2005 AN: 4830

European-Finnish (FIN) AF: 0.209 AC: 2210 AN: 10598

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15188 AN: 67988

Other (OTH) AF: 0.291 AC: 615 AN: 2114

Alfa AF: 0.246 Hom.: 20641

Bravo AF: 0.299

Asia WGS AF: 0.406 AC: 1411 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive congenital ichthyosis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.2
DANN	Uncertain	0.99
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.19
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.069
Sift	Benign	0.70	T
Sift4G	Pathogenic	0.0	D
PromoterAI		0.016	Neutral
gMVP		0.33
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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: rs3027232;

hg19: chr17-8022065;

COSMIC: COSV58554490;

COSMIC: COSV58554490;