17-8115057-GC-AT

Variant names:

• chr17-8115057-GC-AT
• NM_021628.3:c.435-1_435delGCinsAT
• ALOXE3 p.146

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_021628.3(ALOXE3):​c.435-1_435delGCinsAT​(p.146) variant causes a splice acceptor, splice region, synonymous, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALOXE3 NM_021628.3 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• 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 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.056179777 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 38, new splice context is: tggcttcccctgcatggtAGacg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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.435-1_435delGCinsAT	p.146	splice_acceptor splice_region synonymous intron	N/A	NP_067641.2	Q9BYJ1-1
	ALOXE3	NM_001165960.1		c.831-1_831delGCinsAT	p.278	splice_acceptor splice_region synonymous intron	N/A	NP_001159432.1	Q9BYJ1-2
	ALOXE3	NM_001369446.1		c.435-1_435delGCinsAT	p.146	splice_acceptor splice_region synonymous intron	N/A	NP_001356375.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.435-1_435delGCinsAT	p.146	splice_acceptor splice_region synonymous intron	N/A	ENSP00000400581.2	Q9BYJ1-1
	ALOXE3	ENST00000380149.6	TSL:1	c.435-1_435delGCinsAT	p.146	splice_acceptor splice_region synonymous intron	N/A	ENSP00000369494.2	Q9BYJ1-1
	ALOXE3	ENST00000318227.4	TSL:2	c.435-1_435delGCinsAT	p.146	splice_acceptor splice_region synonymous intron	N/A	ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-8018375;