rs3027232

Positions:

• chr17-8118747-G-A

Variant summary

Our verdict is Benign. Variant got -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. 11/16 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

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 -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 id is 1188973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8118747-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOXE3	NM_001165960.1	c.32C>T	p.Pro11Leu	missense_variant	1/16		NP_001159432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOXE3	ENST00000318227.4	c.-365C>T		5_prime_UTR_premature_start_codon_gain_variant	1/16	2		ENSP00000314879.4
ALOXE3	ENST00000318227.4	c.-365C>T		5_prime_UTR_variant	1/16	2		ENSP00000314879.4

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

GnomAD3 exomes AF: 0.334 AC: 47376 AN: 141824 Hom.: 9133 AF XY: 0.330 AC XY: 25021 AN XY: 75862

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 SAS exome AF: 0.403

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

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.517

Gnomad4 SAS exome AF: 0.402

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.276

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

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.291

Alfa AF: 0.245 Hom.: 10069

Bravo AF: 0.299

TwinsUK AF: 0.222 AC: 825

ALSPAC AF: 0.216 AC: 833

ExAC AF: 0.299 AC: 6244

Asia WGS AF: 0.406 AC: 1411 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 26576379) -

Autosomal recessive congenital ichthyosis 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.069
Sift	Benign	0.70	T
Sift4G	Pathogenic	0.0	D
Vest4		0.057
MPC		0.25
ClinPred		0.0083	T
GERP RS		-0.97
gMVP		0.33

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3027232; hg19: chr17-8022065; COSMIC: COSV58554490; COSMIC: COSV58554490;