NM_021628.3:c.2124C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021628.3(ALOXE3):c.2124C>T(p.Ser708Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,385,774 control chromosomes in the GnomAD database, including 128,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12756 hom., cov: 31)

Exomes 𝑓: 0.43 ( 115753 hom. )

Consequence

ALOXE3
NM_021628.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.101

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALOXE3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 17-8096639-G-A is Benign according to our data. Variant chr17-8096639-G-A is described in ClinVar as Benign. ClinVar VariationId is 261424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.101 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOXE3	NM_021628.3 link	c.2124C>T	p.Ser708Ser	synonymous_variant	Exon 16 of 16	ENST00000448843.7	NP_067641.2	Q9BYJ1-1
ALOXE3	NM_001165960.1 link	c.2520C>T	p.Ser840Ser	synonymous_variant	Exon 16 of 16		NP_001159432.1	Q9BYJ1-2
ALOXE3	NM_001369446.1 link	c.2121C>T	p.Ser707Ser	synonymous_variant	Exon 15 of 15		NP_001356375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOXE3	ENST00000448843.7 link	c.2124C>T	p.Ser708Ser	synonymous_variant	Exon 16 of 16	1	NM_021628.3	ENSP00000400581.2		Q9BYJ1-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60491

AN:

151812

Hom.:

12738

Cov.:

show subpopulations

Gnomad AFR

AF:

0.279

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.480

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.413

GnomAD2 exomes

AF:

0.460

AC:

115596

AN:

251468

AF XY:

0.452

show subpopulations

Gnomad AFR exome

AF:

0.273

Gnomad AMR exome

AF:

0.663

Gnomad ASJ exome

AF:

0.456

Gnomad EAS exome

AF:

0.637

Gnomad FIN exome

AF:

0.468

Gnomad NFE exome

AF:

0.414

Gnomad OTH exome

AF:

0.440

GnomAD4 exome

AF:

0.427

AC:

526714

AN:

1233842

Hom.:

115753

Cov.:

AF XY:

0.424

AC XY:

265094

AN XY:

624766

show subpopulations

African (AFR)

AF:

0.270

AC:

7778

AN:

28776

American (AMR)

AF:

0.649

AC:

28785

AN:

44378

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

11116

AN:

24756

East Asian (EAS)

AF:

0.630

AC:

24325

AN:

38622

South Asian (SAS)

AF:

0.393

AC:

32106

AN:

81678

European-Finnish (FIN)

AF:

0.461

AC:

24595

AN:

53344

Middle Eastern (MID)

AF:

0.412

AC:

2191

AN:

5322

European-Non Finnish (NFE)

AF:

0.413

AC:

373621

AN:

904124

Other (OTH)

AF:

0.420

AC:

22197

AN:

52842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

14236

28472

42708

56944

71180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10704

21408

32112

42816

53520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.398

AC:

60544

AN:

151932

Hom.:

12756

Cov.:

AF XY:

0.405

AC XY:

30068

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.279

AC:

11567

AN:

41462

American (AMR)

AF:

0.543

AC:

8298

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1614

AN:

3468

East Asian (EAS)

AF:

0.626

AC:

3211

AN:

5128

South Asian (SAS)

AF:

0.381

AC:

1832

AN:

4812

European-Finnish (FIN)

AF:

0.480

AC:

5061

AN:

10544

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.406

AC:

27579

AN:

67934

Other (OTH)

AF:

0.418

AC:

882

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1806

3612

5419

7225

9031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.409

Hom.:

39571

Bravo

AF:

0.404

Asia WGS

AF:

0.491

AC:

1707

AN:

3478

EpiCase

AF:

0.414

EpiControl

AF:

0.410

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive congenital ichthyosis 3

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

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

-0.69

CADD

Benign

0.28

(source)

DANN

Benign

0.54

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over