17-6998836-G-A

Position:

• chr17-6998836-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000697.3(ALOX12):​c.541G>A​(p.Gly181Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ALOX12 NM_000697.3 missense, splice_region
• Scores: Splicing: ADA: 0.5365
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOX12	NM_000697.3	c.541G>A	p.Gly181Arg	missense_variant, splice_region_variant	4/14	ENST00000251535.11	NP_000688.2
ALOX12-AS1	NR_040089.1	n.233+10960C>T		intron_variant, non_coding_transcript_variant
ALOX12	XM_011523780.3	c.541G>A	p.Gly181Arg	missense_variant, splice_region_variant	4/13		XP_011522082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOX12	ENST00000251535.11	c.541G>A	p.Gly181Arg	missense_variant, splice_region_variant	4/14	1	NM_000697.3	ENSP00000251535	P1
ALOX12-AS1	ENST00000653385.1	n.139+13360C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461842 Hom.: 0 Cov.: 52 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 03, 2023

The c.541G>A (p.G181R) alteration is located in exon 4 (coding exon 4) of the ALOX12 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the glycine (G) at amino acid position 181 to be replaced by an arginine (R). 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	0.29
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.84	P;.
Vest4		0.40
MutPred		0.78		Gain of MoRF binding (P = 0.0124);.;
MVP		0.89
MPC		0.97
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.38
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.51
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: chr17-6902155;