17-8112168-A-T

Position:

• chr17-8112168-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000448843.7(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. 13/20 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 ENST00000448843.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 0.622

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOXE3	NM_021628.3	c.709T>A	p.Leu237Met	missense_variant	7/16	ENST00000448843.7	NP_067641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOXE3	ENST00000448843.7	c.709T>A	p.Leu237Met	missense_variant	7/16	1	NM_021628.3	ENSP00000400581	P1
ALOXE3	ENST00000380149.6	c.709T>A	p.Leu237Met	missense_variant	6/15	1		ENSP00000369494	P1
ALOXE3	ENST00000318227.4	c.709T>A	p.Leu237Met	missense_variant	7/16	2		ENSP00000314879	P1

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

GnomAD3 exomes AF: 0.00499 AC: 1256 AN: 251484 Hom.: 14 AF XY: 0.00618 AC XY: 840 AN XY: 135916

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 SAS exome AF: 0.0248

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

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00401

Gnomad4 OTH exome AF: 0.00392

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

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0211

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00237

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

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ALOXE3: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	- -

Autosomal recessive congenital ichthyosis 3 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.2	.;L;.
MutationTaster	Benign	0.013	A;A;A
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.11	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434235; hg19: chr17-8015486;