rs743646

Variant names:

• chr17-4632946-T-C
• rs743646
• NM_001140.5:c.1455A>G

Variant summary

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

The NM_001140.5(ALOX15):​c.1455A>G​(p.Thr485Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,614,058 control chromosomes in the GnomAD database, including 9,366 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 0.078 (622 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8744 hom.)
• Consequence: ALOX15 NM_001140.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.24
• Publications: 17 publications found

Genes affected

ALOX15 (HGNC:433): (arachidonate 15-lipoxygenase) This gene encodes a member of the lipoxygenase family of proteins. The encoded enzyme acts on various polyunsaturated fatty acid substrates to generate various bioactive lipid mediators such as eicosanoids, hepoxilins, lipoxins, and other molecules. The encoded enzyme and its reaction products have been shown to regulate inflammation and immunity. Multiple pseudogenes of this gene have been identified in the human genome. [provided by RefSeq, Aug 2017]

ALOX15 Gene-Disease associations (from GenCC):

• pregnancy loss, recurrent, susceptibility

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-4.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX15	NM_001140.5	c.1455A>G	p.Thr485Thr	synonymous_variant	Exon 11 of 14	ENST00000293761.8	NP_001131.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX15	ENST00000293761.8	c.1455A>G	p.Thr485Thr	synonymous_variant	Exon 11 of 14	1	NM_001140.5	ENSP00000293761.3
ALOX15	ENST00000570836.6	c.1455A>G	p.Thr485Thr	synonymous_variant	Exon 12 of 15	2		ENSP00000458832.1
ALOX15	ENST00000574640.1	c.1338A>G	p.Thr446Thr	synonymous_variant	Exon 11 of 14	2		ENSP00000460483.1

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11949 AN: 152068 Hom.: 623 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0596

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0746

GnomAD2 exomes AF: 0.0846 AC: 21281 AN: 251444 AF XY: 0.0875

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0955

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0978

GnomAD4 exome AF: 0.105 AC: 153903 AN: 1461872 Hom.: 8744 Cov.: 33 AF XY: 0.105 AC XY: 76332 AN XY: 727240

African (AFR) AF: 0.0171 AC: 573 AN: 33480

American (AMR) AF: 0.0555 AC: 2481 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3158 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0623 AC: 5378 AN: 86258

European-Finnish (FIN) AF: 0.0918 AC: 4905 AN: 53412

Middle Eastern (MID) AF: 0.119 AC: 685 AN: 5766

European-Non Finnish (NFE) AF: 0.117 AC: 130619 AN: 1112006

Other (OTH) AF: 0.101 AC: 6095 AN: 60394

GnomAD4 genome AF: 0.0785 AC: 11945 AN: 152186 Hom.: 622 Cov.: 32 AF XY: 0.0776 AC XY: 5772 AN XY: 74394

African (AFR) AF: 0.0198 AC: 821 AN: 41512

American (AMR) AF: 0.0695 AC: 1063 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 419 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0591 AC: 285 AN: 4826

European-Finnish (FIN) AF: 0.0959 AC: 1017 AN: 10608

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8045 AN: 67978

Other (OTH) AF: 0.0738 AC: 156 AN: 2114

Alfa AF: 0.106 Hom.: 1685

Bravo AF: 0.0741

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.84
DANN	Benign	0.43
PhyloP100		-4.2
Mutation Taster		=100/0	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: rs743646; hg19: chr17-4536241; COSMIC: COSV53399553; COSMIC: COSV53399553;