17-8096638-C-T

Variant names:

• chr17-8096638-C-T
• rs967438626
• NM_021628.3:c.2125G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021628.3(ALOXE3):​c.2125G>A​(p.Val709Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000813 in 1,230,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 0 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18668011).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	NM_021628.3	MANE Select	c.2125G>A	p.Val709Ile	missense	Exon 16 of 16	NP_067641.2	Q9BYJ1-1
	ALOXE3	NM_001165960.1		c.2521G>A	p.Val841Ile	missense	Exon 16 of 16	NP_001159432.1	Q9BYJ1-2
	ALOXE3	NM_001369446.1		c.2122G>A	p.Val708Ile	missense	Exon 15 of 15	NP_001356375.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.2125G>A	p.Val709Ile	missense	Exon 16 of 16	ENSP00000400581.2	Q9BYJ1-1
	ALOXE3	ENST00000380149.6	TSL:1	c.2125G>A	p.Val709Ile	missense	Exon 15 of 15	ENSP00000369494.2	Q9BYJ1-1
	ALOXE3	ENST00000318227.4	TSL:2	c.2125G>A	p.Val709Ile	missense	Exon 16 of 16	ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000813 AC: 10 AN: 1230608 Hom.: 0 Cov.: 19 AF XY: 0.0000112 AC XY: 7 AN XY: 623264

African (AFR) AF: 0.00 AC: 0 AN: 28714

American (AMR) AF: 0.00 AC: 0 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24720

East Asian (EAS) AF: 0.00 AC: 0 AN: 38588

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5326

European-Non Finnish (NFE) AF: 0.00000777 AC: 7 AN: 901184

Other (OTH) AF: 0.0000190 AC: 1 AN: 52684

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.0038
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.72	N
PhyloP100		2.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.27
Sift	Benign	0.23	T
Sift4G	Benign	0.41	T
Polyphen		0.93	P
Vest4		0.16
MutPred		0.48		Gain of glycosylation at S708 (P = 0.0929)
MVP		0.74
MPC		0.11
ClinPred		0.71	D
GERP RS		4.4
Varity_R		0.066
gMVP		0.52

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

Other links and lift over

dbSNP: rs967438626; hg19: chr17-7999956;