17-8096516-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021628.3(ALOXE3):c.*111T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 747,936 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (45 hom.)
• Consequence: ALOXE3 NM_021628.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.230

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-8096516-A-G is Benign according to our data. Variant chr17-8096516-A-G is described in ClinVar as [Benign]. Clinvar id is 325952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.*111T>C		3_prime_UTR_variant	16/16	ENST00000448843.7
ALOXE3	NM_001165960.1	c.*111T>C		3_prime_UTR_variant	16/16
ALOXE3	NM_001369446.1	c.*111T>C		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.*111T>C		3_prime_UTR_variant	16/16	1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.*111T>C		3_prime_UTR_variant	15/15	1		P1
ALOXE3	ENST00000318227.4	c.*111T>C		3_prime_UTR_variant	16/16	2		P1
ALOXE3	ENST00000583808.1	n.484T>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2987 AN: 152202 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00267 AC: 1589 AN: 595616 Hom.: 45 Cov.: 5 AF XY: 0.00208 AC XY: 669 AN XY: 322266

Gnomad4 AFR exome AF: 0.0690

Gnomad4 AMR exome AF: 0.00464

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.00587

GnomAD4 genome AF: 0.0196 AC: 2990 AN: 152320 Hom.: 102 Cov.: 32 AF XY: 0.0188 AC XY: 1402 AN XY: 74484

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0139 Hom.: 13

Bravo AF: 0.0225

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive congenital ichthyosis 3 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.7
Dann	Benign	0.58

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: rs75605551; hg19: chr17-7999834;