NM_001139.3:c.410T>A

Variant names:

• chr17-8081130-A-T
• rs397514530
• NM_001139.3:c.410T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001139.3(ALOX12B):​c.410T>A​(p.Ile137Asn) 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 1,461,702 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALOX12B NM_001139.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.65
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• self-healing collodion baby

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000214999 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Trascript score misZ: 1.7573 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive congenital ichthyosis 2, self-healing collodion baby, congenital non-bullous ichthyosiform erythroderma, lamellar ichthyosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX12B	NM_001139.3	c.410T>A	p.Ile137Asn	missense_variant	Exon 3 of 15	ENST00000647874.1	NP_001130.1
LOC107985075	XR_001752778.2	n.1403A>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX12B	ENST00000647874.1	c.410T>A	p.Ile137Asn	missense_variant	Exon 3 of 15		NM_001139.3	ENSP00000497784.1
ENSG00000214999	ENST00000399413.3	n.1369A>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
ENSG00000214999	ENST00000763133.1	n.55-64A>T		intron_variant	Intron 1 of 2
ENSG00000214999	ENST00000763134.1	n.67-64A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461702 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 2 Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Nov 01, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALOX12B c.410T>A (p.Ile137Asn) results in a non-conservative amino acid change located in the Lipoxygenase, C-terminal domain (IPR013819) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250776 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.410T>A has been reported in the literature in one individual affected with autosomal recessive congenital ichthyoses (Harting_2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19131948, 18347291, 33435499, 36003334). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Jan 26, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I137N variant in the ALOX12B gene has been reported previously in a patient with ichthyosiform erythroderma who was also heterozygous for a second variant (Harting et al., 2008). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I137N variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret I137N as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		0.77	P;P
Vest4		0.54
MutPred		0.93		Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);
MVP		0.92
MPC		1.4
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.75
gMVP		0.85
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs397514530; hg19: chr17-7984448;