Genetic Variant NM_001139.3:c.1990G>C (chr17-8072887-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM2PP3_ModeratePP5_Moderate

The NM_001139.3(ALOX12B):c.1990G>C(p.Ala664Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALOX12B
NM_001139.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -2.15

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1

Transcript NM_001139.3 (ALOX12B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 17-8072887-C-G is Pathogenic according to our data. Variant chr17-8072887-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3768680.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX12B	NM_001139.3 link	c.1990G>C	p.Ala664Pro	missense_variant	Exon 15 of 15	ENST00000647874.1	NP_001130.1	O75342

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX12B	ENST00000647874.1 link	c.1990G>C	p.Ala664Pro	missense_variant	Exon 15 of 15	NM_001139.3	ENSP00000497784.1	O75342
ALOX12B	ENST00000649809.1 link	c.1054G>C	p.Ala352Pro	missense_variant	Exon 8 of 8		ENSP00000496845.1	A0A3B3IRK2
ALOX12B	ENST00000650441.1 link	n.413G>C		non_coding_transcript_exon_variant	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727216

show subpopulations

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lamellar ichthyosis

Pathogenic:1

Feb 28, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALOX12B c.1990G>C (p.Ala664Pro) results in a non-conservative amino acid change located in the Lipoxygenase iron-binding catalytic domain profile (IPR013819) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251214 control chromosomes. c.1990G>C has been reported in the literature in individuals affected with Lamellar Ichthyosis (Eckl_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Eckl_2005). The following publication have been ascertained in the context of this evaluation (PMID: 16116617). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;D;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.84

.;T;T

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.1

D;.;.

REVEL

Uncertain

0.58

Sift

Benign

0.055

T;.;.

Sift4G

Benign

0.12

T;.;.

Polyphen

0.84

P;P;.

Vest4

0.71

MutPred

0.87

Gain of disorder (P = 0.0272);Gain of disorder (P = 0.0272);.;

MVP

0.77

MPC

1.1

ClinPred

0.79

GERP RS

-1.9

Varity_R

0.74

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over