Genetic Variant ALOX5:c.-180_-169delGCGGGGGCGGGG (chr10-45374099-TGCGGGGGCGGGG-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000698.5(ALOX5):c.-180_-169delGCGGGGGCGGGG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 821,896 control chromosomes in the GnomAD database, including 3,443 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 2469 hom., cov: 22)

Exomes 𝑓: 0.0099 ( 974 hom. )

Consequence

ALOX5
NM_000698.5 upstream_gene

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.984

Publications

13 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX5	NM_000698.5 link	c.-180_-169delGCGGGGGCGGGG		upstream_gene_variant		ENST00000374391.7	NP_000689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX5	ENST00000374391.7 link	c.-180_-169delGCGGGGGCGGGG		upstream_gene_variant		1	NM_000698.5	ENSP00000363512.2
ALOX5	ENST00000542434.5 link	c.-180_-169delGCGGGGGCGGGG		upstream_gene_variant		1		ENSP00000437634.1

Frequencies

GnomAD3 genomes

AF:

0.0995

AC:

14902

AN:

149838

Hom.:

2464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.342

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.000826

Gnomad SAS

AF:

0.00425

Gnomad FIN

AF:

0.0000969

Gnomad MID

AF:

0.0194

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.0786

GnomAD4 exome

AF:

0.00992

AC:

6668

AN:

671956

Hom.:

974

AF XY:

0.00908

AC XY:

2955

AN XY:

325606

show subpopulations

African (AFR)

AF:

0.355

AC:

4741

AN:

13348

American (AMR)

AF:

0.0285

AC:

203

AN:

7114

Ashkenazi Jewish (ASJ)

AF:

0.00224

AC:

AN:

10714

East Asian (EAS)

AF:

0.00182

AC:

AN:

21396

South Asian (SAS)

AF:

0.00652

AC:

AN:

12726

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

20676

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

2088

European-Non Finnish (NFE)

AF:

0.00144

AC:

797

AN:

555264

Other (OTH)

AF:

0.0264

AC:

755

AN:

28630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

216

432

649

865

1081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.0996

AC:

14940

AN:

149940

Hom.:

2469

Cov.:

AF XY:

0.0948

AC XY:

6928

AN XY:

73116

show subpopulations

African (AFR)

AF:

0.342

AC:

14001

AN:

40926

American (AMR)

AF:

0.0399

AC:

605

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

3448

East Asian (EAS)

AF:

0.000829

AC:

AN:

4826

South Asian (SAS)

AF:

0.00404

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.0000969

AC:

AN:

10318

Middle Eastern (MID)

AF:

0.0208

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00190

AC:

128

AN:

67294

Other (OTH)

AF:

0.0811

AC:

169

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

471

941

1412

1882

2353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.000457

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.98

Splicing

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