17-6996913-G-A

Variant summary

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

The NM_000697.3(ALOX12):c.223G>A(p.Ala75Thr) 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: 33)
• Consequence: ALOX12 NM_000697.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

ALOX12 (HGNC:429): (arachidonate 12-lipoxygenase, 12S type) This gene encodes a member of the lipoxygenase family of proteins. The encoded enzyme acts on different polyunsaturated fatty acid substrates to generate bioactive lipid mediators including eicosanoids and lipoxins. The encoded enzyme and its reaction products have been shown to regulate platelet function. Elevated expression of this gene has been observed in pancreatic islets derived from human diabetes patients. Allelic variants in this gene may be associated with susceptibility to toxoplasmosis. Multiple pseudogenes of this gene have been identified in the human genome. [provided by RefSeq, Aug 2017]

ALOX12-AS1 (HGNC:51342): (ALOX12 antisense RNA 1)

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
ALOX12	NM_000697.3	c.223G>A	p.Ala75Thr	missense_variant	2/14	ENST00000251535.11
ALOX12-AS1	NR_040089.1	n.234-11373C>T		intron_variant, non_coding_transcript_variant
ALOX12	XM_011523780.3	c.223G>A	p.Ala75Thr	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOX12	ENST00000251535.11	c.223G>A	p.Ala75Thr	missense_variant	2/14	1	NM_000697.3	P1
ALOX12-AS1	ENST00000653385.1	n.139+15283C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2023

The c.223G>A (p.A75T) alteration is located in exon 2 (coding exon 2) of the ALOX12 gene. This alteration results from a G to A substitution at nucleotide position 223, causing the alanine (A) at amino acid position 75 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	0.0042	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.86	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.25
Sift	Benign	0.14	T
Sift4G	Benign	0.21	T
Polyphen		0.97	D
Vest4		0.49
MutPred		0.51		Loss of catalytic residue at A75 (P = 0.0084);
MVP		0.80
MPC		0.74
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.45

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

Other links and lift over

dbSNP: rs1908468824; hg19: chr17-6900232; COSMIC: COSV99278241; COSMIC: COSV99278241;