rs199766569

Positions:

chr17-8075687-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001139.3(ALOX12B):c.1562A>G(p.Tyr521Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,613,930 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 (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ALOX12B
NM_001139.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 5.57

Variant links:

Genes affected

ALOX12B (HGNC:430): (arachidonate 12-lipoxygenase, 12R type) This gene encodes an enzyme involved in the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid. Mutations in this gene are associated with nonbullous congenital ichthyosiform erythroderma. [provided by RefSeq, Sep 2015]

ALOX12B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 17-8075687-T-C is Pathogenic according to our data. Variant chr17-8075687-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8075687-T-C is described in Lovd as [Pathogenic]. Variant chr17-8075687-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOX12B	NM_001139.3 linkuse as main transcript	c.1562A>G	p.Tyr521Cys	missense_variant	12/15	ENST00000647874.1	NP_001130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ALOX12B	ENST00000647874.1 linkuse as main transcript	c.1562A>G	p.Tyr521Cys	missense_variant	12/15		NM_001139.3	ENSP00000497784	P1
ALOX12B	ENST00000649809.1 linkuse as main transcript	c.626A>G	p.Tyr209Cys	missense_variant	5/8			ENSP00000496845
ALOX12B	ENST00000577351.5 linkuse as main transcript	n.479+488A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251486

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000132

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 2

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2014	The Tyr521Cys variant in ALOX12B has been reported in 8 individuals with clinical features of Autosomal recessive congenital ichthyosis. Four of these individuals were homozygous for this variant, and 3 were compound heterozygous with a second variant in ALOX12B (Eckl, 2005; Valhquist, 2010). This variant was not identified in large population studies. Studies have shown that this variant impacts protein function (Eckl 2009); however this in vitro assay may not accurately represent biological function. Computational analyses suggest that the p.Tyr521Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM1, PM2, PP2, PP3, PP4, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Jan 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ALOX12B c.1562A>G (p. Tyr521Cys) variant has been reported in at least six studies in which it is reported in a total of ten individuals with varying degrees of ichthyosis including four in a homozygous state, five in a compound heterozygous state, and one in a heterozygous state where a second variant was not identified (Eckl et al. 2005; Eckl et al. 2009; Vahlquist et al. 2010; Suresh et al. 2015). The p.Tyr521Cys variant was absent from 390 controls and is reported at a frequency of 0.00060 in the European Finnish population of the Exome Aggregation Consortium. Functional analysis in HEK-293 cells revealed that the variant resulted in protein expression levels comparable to wild type, but complete loss of enzymatic activity (Eckl et al. 2005; Eckl et al. 2009). Based on the evidence, the p.Tyr521Cys variant is classified as pathogenic for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2010	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2021	Published functional studies demonstrate this variant results in complete loss of enzymatic activity (Eckl et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19131948, 22622417, 31230075, 19890349, 25998749, 29444371, 23290633, 31168818, 31589614, 33726816, 27025581, 16116617) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 521 of the ALOX12B protein (p.Tyr521Cys). This variant is present in population databases (rs199766569, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 16116617, 27025581, 31168818). ClinVar contains an entry for this variant (Variation ID: 39546). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALOX12B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 04, 2022

Variant summary: ALOX12B c.1562A>G (p.Tyr521Cys) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain (IPR013819) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251486 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALOX12B causing Lamellar Ichthyosis (0.00019 vs 0.0009), allowing no conclusion about variant significance. c.1562A>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Lamellar Ichthyosis (example, Pigg_2016, Eckl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific traceable experimental evidence demonstrating an impact on protein function has been reported. Although one study reported no enzyme activity, the primary data supporting this evidence were not presented (Eckl_2005). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.5

D;.;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.96

MutPred

0.98

Gain of catalytic residue at S523 (P = 0.0553);Gain of catalytic residue at S523 (P = 0.0553);.;

MVP

0.98

MPC

1.7

ClinPred

0.99

GERP RS

4.4

Varity_R

0.94

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over