17-8072811-T-C

Position:

• chr17-8072811-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001139.3(ALOX12B):​c.2066A>G​(p.Tyr689Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 3.74

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOX12B	NM_001139.3	c.2066A>G	p.Tyr689Cys	missense_variant	15/15	ENST00000647874.1	NP_001130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOX12B	ENST00000647874.1	c.2066A>G	p.Tyr689Cys	missense_variant	15/15		NM_001139.3	ENSP00000497784	P1
ALOX12B	ENST00000649809.1	c.1130A>G	p.Tyr377Cys	missense_variant	8/8			ENSP00000496845
ALOX12B	ENST00000650441.1	n.489A>G		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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.2066A>G (p.Y689C) alteration is located in exon 15 (coding exon 15) of the ALOX12B gene. This alteration results from a A to G substitution at nucleotide position 2066, causing the tyrosine (Y) at amino acid position 689 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.6	D;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.65
MutPred		0.79		Loss of stability (P = 0.3261);Loss of stability (P = 0.3261);.;
MVP		0.94
MPC		1.7
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.86
gMVP		0.95

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: chr17-7976129; COSMIC: COSV100047121; COSMIC: COSV100047121;