10-45374099-TGCGGGGGCGGGGGCGGGGGCGGGG-TGCGGGGGCGGGGGCGGGGGCGGGGGCGGGGGCGGGG

Variant names:

• chr10-45374099-T-TGCGGGGGCGGGG
• rs59439148
• NM_000698.5:c.-181_-180insGCGGGGGCGGGG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000698.5(ALOX5):​c.-181_-180insGCGGGGGCGGGG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 821,954 control chromosomes in the GnomAD database, including 11 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0051 (10 hom., cov: 22)
  • Exomes 𝑓: 0.00072 (1 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 772 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 769 AN: 149884 Hom.: 10 Cov.: 22

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0748

Gnomad AMR AF: 0.00521

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00950

Gnomad SAS AF: 0.00212

Gnomad FIN AF: 0.0000969

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00208

Gnomad OTH AF: 0.00533

GnomAD4 exome AF: 0.000723 AC: 486 AN: 671966 Hom.: 1 AF XY: 0.000700 AC XY: 228 AN XY: 325604

Gnomad4 AFR exome AF: 0.00397

Gnomad4 AMR exome AF: 0.00225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00416

Gnomad4 SAS exome AF: 0.000629

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.000470

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00515 AC: 772 AN: 149988 Hom.: 10 Cov.: 22 AF XY: 0.00484 AC XY: 354 AN XY: 73136

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00521

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00953

Gnomad4 SAS AF: 0.00213

Gnomad4 FIN AF: 0.0000969

Gnomad4 NFE AF: 0.00208

Gnomad4 OTH AF: 0.00528

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;