NM_000698.5:c.-181_-180insGCGGGGGCGGGG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 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 0.0051 (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
• 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 772 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_-180insGCGGGGGCGGGG		upstream_gene	N/A	NP_000689.1	P09917-1
	ALOX5	NM_001320861.2		c.-181_-180insGCGGGGGCGGGG		upstream_gene	N/A	NP_001307790.1
	ALOX5	NM_001256153.3		c.-181_-180insGCGGGGGCGGGG		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_-180insGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000363512.2	P09917-1
	ALOX5	ENST00000542434.5	TSL:1	c.-181_-180insGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000437634.1	P09917-2
	ALOX5	ENST00000851643.1		c.-181_-180insGCGGGGGCGGGG		upstream_gene	N/A	ENSP00000521702.1

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

African (AFR) AF: 0.00397 AC: 53 AN: 13362

American (AMR) AF: 0.00225 AC: 16 AN: 7110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10714

East Asian (EAS) AF: 0.00416 AC: 89 AN: 21384

South Asian (SAS) AF: 0.000629 AC: 8 AN: 12728

European-Finnish (FIN) AF: 0.000193 AC: 4 AN: 20674

Middle Eastern (MID) AF: 0.00287 AC: 6 AN: 2090

European-Non Finnish (NFE) AF: 0.000470 AC: 261 AN: 555272

Other (OTH) AF: 0.00171 AC: 49 AN: 28632

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

African (AFR) AF: 0.0102 AC: 418 AN: 40972

American (AMR) AF: 0.00521 AC: 79 AN: 15176

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

East Asian (EAS) AF: 0.00953 AC: 46 AN: 4826

South Asian (SAS) AF: 0.00213 AC: 10 AN: 4700

European-Finnish (FIN) AF: 0.0000969 AC: 1 AN: 10318

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.00208 AC: 140 AN: 67294

Other (OTH) AF: 0.00528 AC: 11 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;