NM_021628.3:c.709T>A

Variant names:

• chr17-8112168-A-T
• rs121434235
• NM_021628.3:c.709T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021628.3(ALOXE3):​c.709T>A​(p.Leu237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,614,172 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (61 hom.)
• Consequence: ALOXE3 NM_021628.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 0.622
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029626489).
• BP6: Variant 17-8112168-A-T is Benign according to our data. Variant chr17-8112168-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00287 (437/152300) while in subpopulation SAS AF = 0.0211 (102/4826). AF 95% confidence interval is 0.0178. There are 4 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.709T>A	p.Leu237Met	missense	Exon 7 of 16	NP_067641.2	Q9BYJ1-1
	ALOXE3	NM_001165960.1		c.1105T>A	p.Leu369Met	missense	Exon 7 of 16	NP_001159432.1	Q9BYJ1-2
	ALOXE3	NM_001369446.1		c.706T>A	p.Leu236Met	missense	Exon 6 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.709T>A	p.Leu237Met	missense	Exon 7 of 16	ENSP00000400581.2	Q9BYJ1-1
	ALOXE3	ENST00000380149.6	TSL:1	c.709T>A	p.Leu237Met	missense	Exon 6 of 15	ENSP00000369494.2	Q9BYJ1-1
	ALOXE3	ENST00000318227.4	TSL:2	c.709T>A	p.Leu237Met	missense	Exon 7 of 16	ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 436 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00499 AC: 1256 AN: 251484 AF XY: 0.00618

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00464 AC: 6782 AN: 1461872 Hom.: 61 Cov.: 31 AF XY: 0.00529 AC XY: 3847 AN XY: 727238

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0221 AC: 1907 AN: 86256

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53418

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.00401 AC: 4463 AN: 1111994

Other (OTH) AF: 0.00392 AC: 237 AN: 60396

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00299 AC XY: 223 AN XY: 74470

African (AFR) AF: 0.00123 AC: 51 AN: 41572

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00232

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00558 AC: 677

Asia WGS AF: 0.00895 AC: 32 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Autosomal recessive congenital ichthyosis 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.62
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.36
Sift	Benign	0.20	T
Sift4G	Benign	0.11	T
Polyphen		0.90	P
Vest4		0.35
MVP		0.69
MPC		0.34
ClinPred		0.028	T
GERP RS		-2.5
Varity_R		0.083
gMVP		0.26
Mutation Taster		=93/7	polymorphism

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: rs121434235; hg19: chr17-8015486;