Genetic Variant ALOXE3:p.Ser708Arg (chr17-8096639-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021628.3(ALOXE3):c.2124C>A(p.Ser708Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000809 in 1,235,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S708S) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

ALOXE3
NM_021628.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.101

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOXE3	NM_021628.3 link	c.2124C>A	p.Ser708Arg	missense_variant	Exon 16 of 16	ENST00000448843.7	NP_067641.2	Q9BYJ1-1
ALOXE3	NM_001165960.1 link	c.2520C>A	p.Ser840Arg	missense_variant	Exon 16 of 16		NP_001159432.1	Q9BYJ1-2
ALOXE3	NM_001369446.1 link	c.2121C>A	p.Ser707Arg	missense_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>A	p.Ser708Arg	missense_variant	Exon 16 of 16	1	NM_021628.3	ENSP00000400581.2		Q9BYJ1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.09e-7

AC:

AN:

1235838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

625688

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28804

American (AMR)

AF:

0.00

AC:

AN:

44384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24770

East Asian (EAS)

AF:

0.00

AC:

AN:

38630

South Asian (SAS)

AF:

0.00

AC:

AN:

81716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

905958

Other (OTH)

AF:

0.00

AC:

AN:

52898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

.;D;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.3

.;M;.

PhyloP100

0.10

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.83

MutPred

0.55

.;Loss of glycosylation at S708 (P = 0.0739);.;

MVP

0.74

MPC

0.48

ClinPred

1.0

GERP RS

-9.0

Varity_R

0.94

gMVP

0.96

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over