chr17-8096089-C-T

Position:

• chr17-8096089-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_021628.3(ALOXE3):​c.*538G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 154,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.293

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00279 (425/152322) while in subpopulation SAS AF= 0.0058 (28/4828). AF 95% confidence interval is 0.00412. There are 1 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.*538G>A		3_prime_UTR_variant	16/16	ENST00000448843.7
ALOXE3	NM_001165960.1	c.*538G>A		3_prime_UTR_variant	16/16
ALOXE3	NM_001369446.1	c.*538G>A		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.*538G>A		3_prime_UTR_variant	16/16	1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.*538G>A		3_prime_UTR_variant	15/15	1		P1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00232 AC: 6 AN: 2586 Hom.: 0 Cov.: 0 AF XY: 0.00219 AC XY: 3 AN XY: 1370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00704

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74492

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00376

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00386 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive congenital ichthyosis 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.30

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: rs141745580; hg19: chr17-7999407;