rs2228065

chr10-45425058-G-Achr10-45425058-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000698.5(ALOX5):c.760G>A(p.Glu254Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,613,738 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (148 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (167 hom.)
• Consequence: ALOX5 NM_000698.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003055185).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOX5	NM_000698.5	c.760G>A	p.Glu254Lys	missense_variant	6/14	ENST00000374391.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOX5	ENST00000374391.7	c.760G>A	p.Glu254Lys	missense_variant	6/14	1	NM_000698.5	P1
ALOX5	ENST00000542434.5	c.760G>A	p.Glu254Lys	missense_variant	6/13	1
ALOX5	ENST00000483623.2	n.163G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3782 AN: 151872 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0263

Gnomad SAS AF: 0.00789

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.00939 AC: 2359 AN: 251274 Hom.: 85 AF XY: 0.00789 AC XY: 1071 AN XY: 135812

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0321

Gnomad SAS exome AF: 0.00650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00348 AC: 5082 AN: 1461748 Hom.: 167 Cov.: 31 AF XY: 0.00329 AC XY: 2389 AN XY: 727170

Gnomad4 AFR exome AF: 0.0844

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.00577

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.00795

GnomAD4 genome AF: 0.0249 AC: 3791 AN: 151990 Hom.: 148 Cov.: 32 AF XY: 0.0233 AC XY: 1732 AN XY: 74322

Gnomad4 AFR AF: 0.0826

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0263

Gnomad4 SAS AF: 0.00769

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0205

Alfa AF: 0.00588 Hom.: 57

Bravo AF: 0.0282

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0840 AC: 370

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0111 AC: 1350

Asia WGS AF: 0.0470 AC: 163 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.087
Dann	Benign	0.54
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.054	N
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.11	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.27
Sift	Benign	0.88	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0	.;B
Vest4		0.062
MPC		0.32
ClinPred		0.00077	T
GERP RS		-7.1
Varity_R		0.18
gMVP		0.49

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: rs2228065; hg19: chr10-45920506;