dbSNP rs2228065: ALOX5:p.Glu254Lys (chr10-45425058-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000698.5(ALOX5):c.760G>A(p.Glu254Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,613,738 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.025 ( 148 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 167 hom. )

Consequence

ALOX5
NM_000698.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.250

Publications

33 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003055185).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX5	NM_000698.5 link	c.760G>A	p.Glu254Lys	missense_variant	Exon 6 of 14	ENST00000374391.7	NP_000689.1	P09917-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALOX5	ENST00000374391.7 link	c.760G>A	p.Glu254Lys	missense_variant	Exon 6 of 14	1	NM_000698.5	ENSP00000363512.2	P09917-1
ALOX5	ENST00000542434.5 link	c.760G>A	p.Glu254Lys	missense_variant	Exon 6 of 13	1		ENSP00000437634.1	P09917-2
ALOX5	ENST00000483623.2 link	n.163G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3782

AN:

151872

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0826

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00859

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0263

Gnomad SAS

AF:

0.00789

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0202

GnomAD2 exomes

AF:

0.00939

AC:

2359

AN:

251274

AF XY:

0.00789

show subpopulations

Gnomad AFR exome

AF:

0.0859

Gnomad AMR exome

AF:

0.00341

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0321

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00348

AC:

5082

AN:

1461748

Hom.:

167

Cov.:

AF XY:

0.00329

AC XY:

2389

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0844

AC:

2826

AN:

33480

American (AMR)

AF:

0.00380

AC:

170

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0229

AC:

908

AN:

39700

South Asian (SAS)

AF:

0.00577

AC:

498

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000161

AC:

179

AN:

1111998

Other (OTH)

AF:

0.00795

AC:

480

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

294

588

882

1176

1470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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

AF:

0.0249

AC:

3791

AN:

151990

Hom.:

148

Cov.:

AF XY:

0.0233

AC XY:

1732

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0826

AC:

3420

AN:

41412

American (AMR)

AF:

0.00857

AC:

131

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0263

AC:

136

AN:

5164

South Asian (SAS)

AF:

0.00769

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67928

Other (OTH)

AF:

0.0205

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

175

349

524

698

873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0104

Hom.:

127

Bravo

AF:

0.0282

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0840

AC:

370

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0111

AC:

1350

Asia WGS

AF:

0.0470

AC:

163

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.087

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.29

.;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.054

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.11

N;N

PhyloP100

0.25

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.58

N;N

REVEL

Benign

0.27

Sift

Benign

0.88

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0

.;B

Vest4

0.062

MPC

0.32

ClinPred

0.00077

GERP RS

-7.1

Varity_R

0.18

gMVP

0.49

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over