10-45444169-A-G

Variant names:

• chr10-45444169-A-G
• rs2229136
• NM_000698.5:c.1728A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000698.5(ALOX5):​c.1728A>G​(p.Pro576Pro) 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
• Publications: 26 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: Benign. The variant received -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.

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.1728A>G	p.Pro576Pro	synonymous	Exon 13 of 14	NP_000689.1	P09917-1
	ALOX5	NM_001320861.2		c.1641A>G	p.Pro547Pro	synonymous	Exon 13 of 14	NP_001307790.1
	ALOX5	NM_001256153.3		c.1632A>G	p.Pro544Pro	synonymous	Exon 13 of 14	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.1728A>G	p.Pro576Pro	synonymous	Exon 13 of 14	ENSP00000363512.2	P09917-1
	ALOX5	ENST00000542434.5	TSL:1	c.1674+341A>G		intron	N/A	ENSP00000437634.1	P09917-2
	ALOX5	ENST00000851643.1		c.1764A>G	p.Pro588Pro	synonymous	Exon 13 of 14	ENSP00000521702.1

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

GnomAD2 exomes AF: 0.0575 AC: 9381 AN: 163216 AF XY: 0.0539

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 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

African (AFR) AF: 0.172 AC: 5488 AN: 31884

American (AMR) AF: 0.0403 AC: 1484 AN: 36782

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 968 AN: 25174

East Asian (EAS) AF: 0.0871 AC: 3157 AN: 36256

South Asian (SAS) AF: 0.0237 AC: 1884 AN: 79598

European-Finnish (FIN) AF: 0.0759 AC: 3693 AN: 48626

Middle Eastern (MID) AF: 0.0437 AC: 242 AN: 5540

European-Non Finnish (NFE) AF: 0.0690 AC: 74706 AN: 1082132

Other (OTH) AF: 0.0654 AC: 3801 AN: 58150

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

African (AFR) AF: 0.168 AC: 6989 AN: 41560

American (AMR) AF: 0.0649 AC: 993 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3470

East Asian (EAS) AF: 0.0518 AC: 268 AN: 5170

South Asian (SAS) AF: 0.0221 AC: 107 AN: 4832

European-Finnish (FIN) AF: 0.0688 AC: 731 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0668 AC: 4543 AN: 68002

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

Alfa AF: 0.0757 Hom.: 277

Bravo AF: 0.0958

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.092
DANN	Benign	0.62
PhyloP100		-4.9
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229136; hg19: chr10-45939617; COSMIC: COSV108223042; COSMIC: COSV108223042;