Genetic Variant NM_021628.3:c.435-131G>A (chr17-8115188-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021628.3(ALOXE3):c.435-131G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.099 in 1,285,510 control chromosomes in the GnomAD database, including 6,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1257 hom., cov: 32)

Exomes 𝑓: 0.096 ( 5707 hom. )

Consequence

ALOXE3
NM_021628.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.511

Variant links:

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]

ALOXE3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-8115188-C-T is Benign according to our data. Variant chr17-8115188-C-T is described in ClinVar as [Benign]. Clinvar id is 1255270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOXE3	NM_021628.3 link	c.435-131G>A		intron_variant	Intron 4 of 15	ENST00000448843.7	NP_067641.2	Q9BYJ1-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALOXE3	ENST00000448843.7 link	c.435-131G>A	intron_variant	Intron 4 of 15	1	NM_021628.3	ENSP00000400581.2	Q9BYJ1-1
ALOXE3	ENST00000380149.6 link	c.435-131G>A	intron_variant	Intron 3 of 14	1		ENSP00000369494.2	Q9BYJ1-1J3KPH2
ALOXE3	ENST00000318227.4 link	c.435-131G>A	intron_variant	Intron 4 of 15	2		ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18065

AN:

152170

Hom.:

1255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.0950

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.0422

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.0753

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.0921

Gnomad OTH

AF:

0.124

GnomAD4 exome

AF:

0.0964

AC:

109229

AN:

1133222

Hom.:

5707

AF XY:

0.0978

AC XY:

56051

AN XY:

572896

show subpopulations

Gnomad4 AFR exome

AF:

0.189

Gnomad4 AMR exome

AF:

0.0654

Gnomad4 ASJ exome

AF:

0.164

Gnomad4 EAS exome

AF:

0.0434

Gnomad4 SAS exome

AF:

0.120

Gnomad4 FIN exome

AF:

0.0852

Gnomad4 NFE exome

AF:

0.0930

Gnomad4 OTH exome

AF:

0.107

GnomAD4 genome

AF:

0.119

AC:

18078

AN:

152288

Hom.:

1257

Cov.:

AF XY:

0.118

AC XY:

8812

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.186

Gnomad4 AMR

AF:

0.0948

Gnomad4 ASJ

AF:

0.163

Gnomad4 EAS

AF:

0.0423

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.0753

Gnomad4 NFE

AF:

0.0921

Gnomad4 OTH

AF:

0.123

Alfa

AF:

0.103

Hom.:

1142

Bravo

AF:

0.123

Asia WGS

AF:

0.0960

AC:

331

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over