10-45374099-TGCGGGGGCGGGGGCGGGGGCGGGG-TGCGGGGGCGGGGGCGGGGGCGGGGGCGGGG

Variant names:

• chr10-45374099-T-TGCGGGG
• rs59439148
• NM_000698.5:c.-181_-180insGCGGGG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000698.5(ALOX5):​c.-181_-180insGCGGGG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 821,846 control chromosomes in the GnomAD database, including 295 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (96 hom., cov: 22)
  • Exomes 𝑓: 0.0098 (199 hom.)
• Consequence: ALOX5 NM_000698.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292

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

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX5	NM_000698.5	c.-181_-180insGCGGGG		upstream_gene_variant		ENST00000374391.7	NP_000689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX5	ENST00000374391.7	c.-181_-180insGCGGGG		upstream_gene_variant		1	NM_000698.5	ENSP00000363512.2
ALOX5	ENST00000542434.5	c.-181_-180insGCGGGG		upstream_gene_variant		1		ENSP00000437634.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3546 AN: 149880 Hom.: 99 Cov.: 22

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0160

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0523

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0272

GnomAD4 exome AF: 0.00981 AC: 6591 AN: 671864 Hom.: 199 AF XY: 0.0101 AC XY: 3281 AN XY: 325566

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.0276

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0236 AC: 3539 AN: 149982 Hom.: 96 Cov.: 22 AF XY: 0.0249 AC XY: 1823 AN XY: 73138

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.0160

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.0521

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0269

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59439148; hg19: chr10-45869547;