10-45374099-TGCGGGGGCGGGGGCGGGGGCGGGG-TGCGGGGGCGGGGGCGGGGGCGGGGGCGGGGGCGGGGGCGGGGGCGGGG

Variant names:

• chr10-45374099-T-TGCGGGGGCGGGGGCGGGGGCGGGG
• rs59439148
• NM_000698.5:c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG

Variant summary

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

The NM_000698.5(ALOX5):​c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 821,996 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: ALOX5 NM_000698.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292
• Publications: 13 publications found

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]

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOX5	NM_000698.5	MANE Select	c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	NP_000689.1	P09917-1
	ALOX5	NM_001320861.2		c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	NP_001307790.1
	ALOX5	NM_001256153.3		c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	NP_001243082.1	P09917-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOX5	ENST00000374391.7	TSL:1 MANE Select	c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000363512.2	P09917-1
	ALOX5	ENST00000542434.5	TSL:1	c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000437634.1	P09917-2
	ALOX5	ENST00000851643.1		c.-181_-180insGCGGGGGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000521702.1

Frequencies

GnomAD3 genomes AF: 0.000193 AC: 29 AN: 149888 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000387 AC: 26 AN: 672006 Hom.: 0 AF XY: 0.0000522 AC XY: 17 AN XY: 325626

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

African (AFR) AF: 0.00 AC: 0 AN: 13364

American (AMR) AF: 0.00 AC: 0 AN: 7114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10716

East Asian (EAS) AF: 0.00122 AC: 26 AN: 21390

South Asian (SAS) AF: 0.00 AC: 0 AN: 12728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 555294

Other (OTH) AF: 0.00 AC: 0 AN: 28634

⚠️ 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.

GnomAD4 genome AF: 0.000200 AC: 30 AN: 149990 Hom.: 0 Cov.: 22 AF XY: 0.000164 AC XY: 12 AN XY: 73140

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

African (AFR) AF: 0.000171 AC: 7 AN: 40976

American (AMR) AF: 0.000395 AC: 6 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00290 AC: 14 AN: 4820

South Asian (SAS) AF: 0.000425 AC: 2 AN: 4702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67296

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000194359), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29

Splicing

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

Other links and lift over

dbSNP: rs59439148; hg19: chr10-45869547;