17-4639462-C-G

Variant names:

• chr17-4639462-C-G
• rs41439950
• NM_001140.5:c.305G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001140.5(ALOX15):​c.305G>C​(p.Gly102Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G102V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: ALOX15 NM_001140.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.892
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX15	NM_001140.5	c.305G>C	p.Gly102Ala	missense_variant	Exon 2 of 14	ENST00000293761.8	NP_001131.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX15	ENST00000293761.8	c.305G>C	p.Gly102Ala	missense_variant	Exon 2 of 14	1	NM_001140.5	ENSP00000293761.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;.;T
Eigen	Benign	0.094
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.79	.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.8	M;M;.;.
PhyloP100		0.89
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	.;D;.;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	.;D;.;.
Sift4G	Uncertain	0.0090	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.34
MVP		0.80
MPC		0.44
ClinPred		0.99	D
GERP RS		3.8
PromoterAI		0.14	Neutral
Varity_R		0.77
gMVP		0.46

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: rs41439950; hg19: chr17-4542757;