rs113539426

chr17-8111545-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021628.3(ALOXE3):c.785-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,613,964 control chromosomes in the GnomAD database, including 706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (67 hom., cov: 32)
  • Exomes 𝑓: 0.026 (639 hom.)
• Consequence: ALOXE3 NM_021628.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.01

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 (BayesDel_noAF=-0.8).
• BP6: Variant 17-8111545-G-A is Benign according to our data. Variant chr17-8111545-G-A is described in ClinVar as [Benign]. Clinvar id is 261425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8111545-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.785-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000448843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.785-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.785-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1		P1
ALOXE3	ENST00000318227.4	c.785-14C>T		splice_polypyrimidine_tract_variant, intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3493 AN: 152224 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00593

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0302

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0238 AC: 5991 AN: 251248 Hom.: 119 AF XY: 0.0242 AC XY: 3288 AN XY: 135834

Gnomad AFR exome AF: 0.00450

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0258 AC: 37673 AN: 1461622 Hom.: 639 Cov.: 32 AF XY: 0.0258 AC XY: 18760 AN XY: 727126

Gnomad4 AFR exome AF: 0.00574

Gnomad4 AMR exome AF: 0.0206

Gnomad4 ASJ exome AF: 0.0656

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0298

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0229 AC: 3488 AN: 152342 Hom.: 67 Cov.: 32 AF XY: 0.0229 AC XY: 1709 AN XY: 74494

Gnomad4 AFR AF: 0.00591

Gnomad4 AMR AF: 0.0280

Gnomad4 ASJ AF: 0.0677

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00953

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0301

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0325 Hom.: 33

Bravo AF: 0.0227

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, 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 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	10
Dann	Benign	0.46

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: rs113539426; hg19: chr17-8014863;