17-8072789-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001139.3(ALOX12B):c.2088G>C(p.Glu696Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALOX12B NM_001139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.843

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOX12B	NM_001139.3	c.2088G>C	p.Glu696Asp	missense_variant	15/15	ENST00000647874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOX12B	ENST00000647874.1	c.2088G>C	p.Glu696Asp	missense_variant	15/15		NM_001139.3	P1
ALOX12B	ENST00000649809.1	c.1152G>C	p.Glu384Asp	missense_variant	8/8
ALOX12B	ENST00000650441.1	n.511G>C		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

This missense change has been observed in individual(s) with congenital ichthyosis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 696 of the ALOX12B protein (p.Glu696Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.6	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.017	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.37
MutPred		0.61		Loss of catalytic residue at E696 (P = 0.1744);Loss of catalytic residue at E696 (P = 0.1744);.;
MVP		0.92
MPC		1.4
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.69
gMVP		0.93

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.

Other links and lift over

hg19: chr17-7976107;