Genetic Variant ALOX5:c.-180_-163delGCGGGGGCGGGGGCGGGG (chr10-45374099-TGCGGGGGCGGGGGCGGGG-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000698.5(ALOX5):c.-180_-163delGCGGGGGCGGGGGCGGGG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 821,978 control chromosomes in the GnomAD database, including 3 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 0.00069 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00097 ( 3 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX5	NM_000698.5 link	c.-180_-163delGCGGGGGCGGGGGCGGGG		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_-163delGCGGGGGCGGGGGCGGGG		upstream_gene_variant		1	NM_000698.5	ENSP00000363512.2
ALOX5	ENST00000542434.5 link	c.-180_-163delGCGGGGGCGGGGGCGGGG		upstream_gene_variant		1		ENSP00000437634.1

Frequencies

GnomAD3 genomes

AF:

0.000687

AC:

103

AN:

149892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000416

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000194

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000973

AC:

654

AN:

671984

Hom.:

AF XY:

0.000946

AC XY:

308

AN XY:

325616

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

13364

American (AMR)

AF:

0.000141

AC:

AN:

7114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10716

East Asian (EAS)

AF:

0.0000935

AC:

AN:

21396

South Asian (SAS)

AF:

0.0000786

AC:

AN:

12728

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

20676

Middle Eastern (MID)

AF:

0.000478

AC:

AN:

2090

European-Non Finnish (NFE)

AF:

0.00113

AC:

628

AN:

555266

Other (OTH)

AF:

0.000524

AC:

AN:

28634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000687

AC:

103

AN:

149994

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

73144

show subpopulations

African (AFR)

AF:

0.000415

AC:

AN:

40976

American (AMR)

AF:

0.000132

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4826

South Asian (SAS)

AF:

0.00

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.000194

AC:

AN:

10318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

67294

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000274

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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10-45374099-TGCGGGGGCGGGGGCGGGGGCGGGG-TGCGGGG

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