17-8096113-A-C

Position:

• chr17-8096113-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_021628.3(ALOXE3):​c.*514T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 156,474 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00357 (544/152282) while in subpopulation NFE AF= 0.00617 (420/68022). AF 95% confidence interval is 0.00569. There are 3 homozygotes in gnomad4. There are 237 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
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.*514T>G		3_prime_UTR_variant	16/16	ENST00000448843.7
ALOXE3	NM_001165960.1	c.*514T>G		3_prime_UTR_variant	16/16
ALOXE3	NM_001369446.1	c.*514T>G		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.*514T>G		3_prime_UTR_variant	16/16	1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.*514T>G		3_prime_UTR_variant	15/15	1		P1

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00358 AC: 15 AN: 4192 Hom.: 0 Cov.: 0 AF XY: 0.00410 AC XY: 9 AN XY: 2196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0250

Gnomad4 NFE exome AF: 0.00515

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74466

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.00617

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00561 Hom.: 2

Bravo AF: 0.00339

Asia WGS AF: 0.000289 AC: 1 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	-0.75
CADD	Benign	7.9
DANN	Benign	0.82

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: rs80223722; hg19: chr17-7999431;