10-45374368-C-A

Variant names:

Variant summary

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

The NM_000698.5(ALOX5):c.89C>A(p.Ala30Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A30G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ALOX5
NM_000698.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

Publications

0 publications found

Variant links:

Genes affected

ALOX5 (HGNC:435): (arachidonate 5-lipoxygenase) This gene encodes a member of the lipoxygenase gene family and plays a dual role in the synthesis of leukotrienes from arachidonic acid. The encoded protein, which is expressed specifically in bone marrow-derived cells, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid, and further to the allylic epoxide 5(S)-trans-7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). Leukotrienes are important mediators of a number of inflammatory and allergic conditions. Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ALOX5 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=0.07403237).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000698.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALOX5	NM_000698.5	MANE Select	c.89C>A	p.Ala30Glu	missense	Exon 1 of 14	NP_000689.1	P09917-1
ALOX5	NM_001320861.2		c.89C>A	p.Ala30Glu	missense	Exon 1 of 14	NP_001307790.1
ALOX5	NM_001256153.3		c.89C>A	p.Ala30Glu	missense	Exon 1 of 14	NP_001243082.1	P09917-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALOX5	ENST00000374391.7	TSL:1 MANE Select	c.89C>A	p.Ala30Glu	missense	Exon 1 of 14	ENSP00000363512.2	P09917-1
ALOX5	ENST00000542434.5	TSL:1	c.89C>A	p.Ala30Glu	missense	Exon 1 of 13	ENSP00000437634.1	P09917-2
ALOX5	ENST00000851643.1		c.89C>A	p.Ala30Glu	missense	Exon 1 of 14	ENSP00000521702.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1397596

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692608

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:

29394

American (AMR)

AF:

0.00

AC:

AN:

34516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24516

East Asian (EAS)

AF:

0.00

AC:

AN:

34202

South Asian (SAS)

AF:

0.00

AC:

AN:

78386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083566

Other (OTH)

AF:

0.00

AC:

AN:

57472

⚠️ 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: 0.225

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

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.073

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.58

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.4

PhyloP100

1.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

1.1

REVEL

Benign

0.094

Sift

Benign

0.89

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.079

MutPred

0.37

Gain of disorder (P = 0.0168)

MVP

0.64

MPC

0.33

ClinPred

0.34

GERP RS

3.3

PromoterAI

0.049

Neutral

(source)

Varity_R

0.29

gMVP

0.42

Mutation Taster

=69/31

polymorphism

(source)

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

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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