dbSNP rs147149459: ALOXE3:p.Pro630Leu (chr17-8103390-G-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PS3PP3PP5_Very_StrongBS1_SupportingBS2_Supporting

The NM_021628.3(ALOXE3):c.1889C>T(p.Pro630Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,614,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915793: Eckl et al. (2005) demonstrated that HEK-293 cells expressing the p.Pro630Leu variant showed a complete loss of enzyme activity." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

ALOXE3
NM_021628.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.48

Publications

23 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
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: Pathogenic. The variant received 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000915793: Eckl et al. (2005) demonstrated that HEK-293 cells expressing the p.Pro630Leu variant showed a complete loss of enzyme activity.; SCV005688766: Functional studies show that p.Pro630Leu results in complete loss of eLOX-3 enzymatic activity in HEK293 cells indicating that this variant impacts protein function (Eckl KM et al., PMID: 16116617).; SCV000329062: Published functional studies demonstrate that P630L results in complete loss of eLOX-3 enzymatic activity (Eckl et al., 2005);; SCV003252132: Experimental studies have shown that this missense change affects ALOXE3 function (PMID: 16116617).; SCV000713481: "In vitro functional studies suggest the variant impacts enzymatic function;" Eckl 2005; SCV002103957: The most pronounced variant effect results in complete loss of normal epidermal lipoxygenase activity (example, Eckl_2005).; SCV004731123: A functional study using HEK293 cells shows that this variant results in a loss of 12R-LOX and eLOX3 enzyme activity (Eckl et al. 2005. PubMed ID: 16116617).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

PP5

Variant 17-8103390-G-A is Pathogenic according to our data. Variant chr17-8103390-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 279677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00182 (2658/1461864) while in subpopulation NFE AF = 0.00232 (2575/1111998). AF 95% confidence interval is 0.00224. There are 2 homozygotes in GnomAdExome4. There are 1282 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021628.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALOXE3	NM_021628.3	MANE Select	c.1889C>T	p.Pro630Leu	missense	Exon 15 of 16	NP_067641.2	Q9BYJ1-1
ALOXE3	NM_001165960.1		c.2285C>T	p.Pro762Leu	missense	Exon 15 of 16	NP_001159432.1	Q9BYJ1-2
ALOXE3	NM_001369446.1		c.1886C>T	p.Pro629Leu	missense	Exon 14 of 15	NP_001356375.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.1889C>T	p.Pro630Leu	missense	Exon 15 of 16	ENSP00000400581.2	Q9BYJ1-1
ALOXE3	ENST00000380149.6	TSL:1	c.1889C>T	p.Pro630Leu	missense	Exon 14 of 15	ENSP00000369494.2	Q9BYJ1-1
ALOXE3	ENST00000318227.4	TSL:2	c.1889C>T	p.Pro630Leu	missense	Exon 15 of 16	ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00103

AC:

259

AN:

251454

AF XY:

0.000986

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00182

AC:

2658

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1282

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00232

AC:

2575

AN:

1111998

Other (OTH)

AF:

0.000911

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

151

303

454

606

757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00100

AC:

153

AN:

152264

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41540

American (AMR)

AF:

0.000327

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00193

AC:

131

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00144

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.00218

EpiControl

AF:

0.00166

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive congenital ichthyosis 3 (7)

not provided (7)

Autosomal recessive congenital ichthyosis (2)

ALOXE3-related disorder (1)

Lamellar ichthyosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PhyloP100

9.5

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-9.6

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MVP

0.99

MPC

0.46

ClinPred

0.98

GERP RS

5.0

Varity_R

0.91

gMVP

0.78

Mutation Taster

=3/97

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over