rs2229136

Positions:

• chr10-45444169-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000698.5(ALOX5):​c.1728A>G​(p.Pro576=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,556,424 control chromosomes in the GnomAD database, including 4,496 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.092 (868 hom., cov: 33)
  • Exomes 𝑓: 0.068 (3628 hom.)
• Consequence: ALOX5 NM_000698.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.92

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-4.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOX5	NM_000698.5	c.1728A>G	p.Pro576=	synonymous_variant	13/14	ENST00000374391.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOX5	ENST00000374391.7	c.1728A>G	p.Pro576=	synonymous_variant	13/14	1	NM_000698.5	P1
ALOX5	ENST00000542434.5	c.1674+341A>G		intron_variant		1
ALOX5	ENST00000481117.1	n.451A>G		non_coding_transcript_exon_variant	3/3	2
ALOX5	ENST00000498461.1	n.559A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0919 AC: 13987 AN: 152164 Hom.: 860 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.0779

GnomAD3 exomes AF: 0.0575 AC: 9381 AN: 163216 Hom.: 357 AF XY: 0.0539 AC XY: 4671 AN XY: 86642

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.0382

Gnomad SAS exome AF: 0.0252

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0627

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0680 AC: 95423 AN: 1404142 Hom.: 3628 Cov.: 32 AF XY: 0.0663 AC XY: 45938 AN XY: 693136

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0403

Gnomad4 ASJ exome AF: 0.0385

Gnomad4 EAS exome AF: 0.0871

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0759

Gnomad4 NFE exome AF: 0.0690

Gnomad4 OTH exome AF: 0.0654

GnomAD4 genome AF: 0.0920 AC: 14012 AN: 152282 Hom.: 868 Cov.: 33 AF XY: 0.0912 AC XY: 6789 AN XY: 74456

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0649

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.0518

Gnomad4 SAS AF: 0.0221

Gnomad4 FIN AF: 0.0688

Gnomad4 NFE AF: 0.0668

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0745 Hom.: 264

Bravo AF: 0.0958

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.092
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229136; hg19: chr10-45939617;