chr17-8111474-C-A

Variant names:

• chr17-8111474-C-A
• rs786205120
• NM_021628.3:c.842G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_021628.3(ALOXE3):​c.842G>T​(p.Gly281Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G281D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.16
• Publications: 4 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-8111474-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432186.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 17-8111474-C-A is Pathogenic according to our data. Variant chr17-8111474-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39548.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	NM_021628.3	MANE Select	c.842G>T	p.Gly281Val	missense	Exon 8 of 16	NP_067641.2
	ALOXE3	NM_001165960.1		c.1238G>T	p.Gly413Val	missense	Exon 8 of 16	NP_001159432.1
	ALOXE3	NM_001369446.1		c.839G>T	p.Gly280Val	missense	Exon 7 of 15	NP_001356375.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.842G>T	p.Gly281Val	missense	Exon 8 of 16	ENSP00000400581.2
	ALOXE3	ENST00000380149.6	TSL:1	c.842G>T	p.Gly281Val	missense	Exon 7 of 15	ENSP00000369494.2
	ALOXE3	ENST00000318227.4	TSL:2	c.842G>T	p.Gly281Val	missense	Exon 8 of 16	ENSP00000314879.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 3 Pathogenic:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of sheet (P = 0.1158)
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.92
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205120; hg19: chr17-8014792;