Genetic Variant NM_000697.3:c.349G>A (chr17-6998520-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000697.3(ALOX12):c.349G>A(p.Gly117Arg) 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 1,461,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALOX12
NM_000697.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.24

Publications

0 publications found

Variant links:

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 links:

MIR497HG (HGNC:39523): (mir-497-195 cluster host gene)

MIR497HG links:

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

ALOX12-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12508905).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000697.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOX12	NM_000697.3	MANE Select	c.349G>A	p.Gly117Arg	missense	Exon 3 of 14	NP_000688.2	P18054
	ALOX12-AS1	NR_040089.1		n.233+11276C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALOX12	ENST00000251535.11	TSL:1 MANE Select	c.349G>A	p.Gly117Arg	missense	Exon 3 of 14	ENSP00000251535.6	P18054
ALOX12	ENST00000915595.1		c.349G>A	p.Gly117Arg	missense	Exon 3 of 14	ENSP00000585654.1
ALOX12	ENST00000480801.1	TSL:3	c.58G>A	p.Gly20Arg	missense	Exon 2 of 5	ENSP00000467033.1	K7ENN9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726870

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111660

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.096

Eigen

Benign

-0.22

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.68

M_CAP

Benign

0.0024

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

PhyloP100

2.2

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.15

REVEL

Benign

0.057

Sift

Benign

0.57

Sift4G

Benign

0.67

Polyphen

0.0010

Vest4

0.42

MutPred

0.41

Gain of catalytic residue at G117 (P = 0.0879)

MVP

0.47

MPC

0.33

ClinPred

0.19

GERP RS

4.5

Varity_R

0.11

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over