10-45374099-TGCGGGGGCGGGGGCGGGGGCGGGG-TGCGGGGGCGGGGGCGGGGGCGGGGGCGGGGGCGGGGGCGGGG

Variant names:

• chr10-45374099-T-TGCGGGGGCGGGGGCGGGG
• rs59439148
• NM_000698.5:c.-181_-180insGCGGGGGCGGGGGCGGGG

Variant summary

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

The NM_000698.5(ALOX5):​c.-181_-180insGCGGGGGCGGGGGCGGGG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 821,980 control chromosomes in the GnomAD database, including 1 homozygotes. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000082 (1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 96 AD gene.

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_-180insGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	NP_000689.1	P09917-1
	ALOX5	NM_001320861.2		c.-181_-180insGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	NP_001307790.1
	ALOX5	NM_001256153.3		c.-181_-180insGCGGGGGCGGGGGCGGGG		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_-180insGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000363512.2	P09917-1
	ALOX5	ENST00000542434.5	TSL:1	c.-181_-180insGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000437634.1	P09917-2
	ALOX5	ENST00000851643.1		c.-181_-180insGCGGGGGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000521702.1

Frequencies

GnomAD3 genomes AF: 0.000627 AC: 94 AN: 149894 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000924

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00620

Gnomad SAS AF: 0.000637

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000223

Gnomad OTH AF: 0.000970

GnomAD4 exome AF: 0.0000818 AC: 55 AN: 671984 Hom.: 1 AF XY: 0.0000952 AC XY: 31 AN XY: 325620

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

African (AFR) AF: 0.000299 AC: 4 AN: 13364

American (AMR) AF: 0.000562 AC: 4 AN: 7114

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

East Asian (EAS) AF: 0.000795 AC: 17 AN: 21384

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20674

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

European-Non Finnish (NFE) AF: 0.0000252 AC: 14 AN: 555288

Other (OTH) AF: 0.000559 AC: 16 AN: 28626

⚠️ 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: 0.000640 AC: 96 AN: 149996 Hom.: 0 Cov.: 22 AF XY: 0.000711 AC XY: 52 AN XY: 73144

African (AFR) AF: 0.000805 AC: 33 AN: 40976

American (AMR) AF: 0.000923 AC: 14 AN: 15176

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

East Asian (EAS) AF: 0.00601 AC: 29 AN: 4826

South Asian (SAS) AF: 0.000638 AC: 3 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: 0.000223 AC: 15 AN: 67296

Other (OTH) AF: 0.000960 AC: 2 AN: 2084

Alfa AF: 0.00 Hom.: 43

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;