rs199545653

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001139.3(ALOX12B):c.1579G>A(p.Val527Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,614,056 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ALOX12B
NM_001139.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.38

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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001139.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

PP5

Variant 17-8075670-C-T is Pathogenic according to our data. Variant chr17-8075670-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOX12B	NM_001139.3 linkuse as main transcript	c.1579G>A	p.Val527Met	missense_variant	12/15	ENST00000647874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ALOX12B	ENST00000647874.1 linkuse as main transcript	c.1579G>A	p.Val527Met	missense_variant	12/15		NM_001139.3	P1
ALOX12B	ENST00000649809.1 linkuse as main transcript	c.643G>A	p.Val215Met	missense_variant	5/8
ALOX12B	ENST00000577351.5 linkuse as main transcript	n.479+505G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251488

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 2

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 19, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Jan 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Ichthyosis, congenital, autosomal recessive 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => found in unrelated patients (PMID:26762237) (PMID:17139268) (PMID:19890349). PM3 => For recessive disorders, detected in trans with a likely pathogenic variant (PMID:26762237). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 527 of the ALOX12B protein (p.Val527Met). This variant is present in population databases (rs199545653, gnomAD 0.02%). This missense change has been observed in individuals with congenital ichthyosis (PMID: 17139268, 27025581). ClinVar contains an entry for this variant (Variation ID: 212729). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALOX12B protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27025581, 17139268, 19890349, 26762237, 34426522, 31168818, 35315045, 33435499) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.91

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

H;H;.

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

D;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.012

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.76

MVP

0.92

MPC

1.5

ClinPred

0.99

GERP RS

4.5

Varity_R

0.81

gMVP

0.83

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