rs121434234

Positions:

• chr17-8110211-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_021628.3(ALOXE3):​c.1186C>A​(p.Arg396Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.82

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_021628.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 17-8110211-G-T is Pathogenic according to our data. Variant chr17-8110211-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3409.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3	c.1186C>A	p.Arg396Ser	missense_variant	10/16	ENST00000448843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7	c.1186C>A	p.Arg396Ser	missense_variant	10/16	1	NM_021628.3	P1
ALOXE3	ENST00000380149.6	c.1186C>A	p.Arg396Ser	missense_variant	9/15	1		P1
ALOXE3	ENST00000318227.4	c.1186C>A	p.Arg396Ser	missense_variant	10/16	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 3 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Jan 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.95
MutPred		0.91		.;Loss of ubiquitination at K392 (P = 0.1079);.;
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434234; hg19: chr17-8013529;