17-8109899-C-T

Variant names:

• chr17-8109899-C-T
• rs151256885
• NM_021628.3:c.1392+17G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021628.3(ALOXE3):​c.1392+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,547,320 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (82 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (109 hom.)
• Consequence: ALOXE3 NM_021628.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.14
• Publications: 5 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-8109899-C-T is Benign according to our data. Variant chr17-8109899-C-T is described in ClinVar as Benign. ClinVar VariationId is 261422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

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.1392+17G>A		intron	N/A	NP_067641.2
	ALOXE3	NM_001165960.1		c.1788+17G>A		intron	N/A	NP_001159432.1
	ALOXE3	NM_001369446.1		c.1389+17G>A		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.1392+17G>A		intron	N/A	ENSP00000400581.2
	ALOXE3	ENST00000380149.6	TSL:1	c.1392+17G>A		intron	N/A	ENSP00000369494.2
	ALOXE3	ENST00000318227.4	TSL:2	c.1392+17G>A		intron	N/A	ENSP00000314879.4

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2845 AN: 152110 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00527 AC: 787 AN: 149462 AF XY: 0.00426

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.00747

GnomAD4 exome AF: 0.00267 AC: 3727 AN: 1395092 Hom.: 109 Cov.: 32 AF XY: 0.00253 AC XY: 1744 AN XY: 688016

African (AFR) AF: 0.0704 AC: 2222 AN: 31544

American (AMR) AF: 0.00311 AC: 111 AN: 35636

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 467 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 35670

South Asian (SAS) AF: 0.000303 AC: 24 AN: 79144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47088

Middle Eastern (MID) AF: 0.0118 AC: 66 AN: 5610

European-Non Finnish (NFE) AF: 0.000359 AC: 387 AN: 1077424

Other (OTH) AF: 0.00778 AC: 450 AN: 57868

GnomAD4 genome AF: 0.0188 AC: 2868 AN: 152228 Hom.: 82 Cov.: 33 AF XY: 0.0185 AC XY: 1377 AN XY: 74432

African (AFR) AF: 0.0629 AC: 2611 AN: 41524

American (AMR) AF: 0.00850 AC: 130 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68002

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00662 Hom.: 5

Bravo AF: 0.0210

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.12
DANN	Benign	0.78
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -1

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

Other links and lift over

dbSNP: rs151256885; hg19: chr17-8013217;