17-4639462-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001140.5(ALOX15):​c.305G>T​(p.Gly102Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000456 in 1,613,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: ALOX15 NM_001140.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.892
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35703248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX15	NM_001140.5	c.305G>T	p.Gly102Val	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>T	p.Gly102Val	missense_variant	Exon 2 of 14	1	NM_001140.5	ENSP00000293761.3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152196 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000343 AC: 86 AN: 250556 AF XY: 0.000420

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000467 AC: 682 AN: 1461224 Hom.: 1 Cov.: 37 AF XY: 0.000464 AC XY: 337 AN XY: 726944

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000291 AC: 13 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86254

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52896

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5764

European-Non Finnish (NFE) AF: 0.000532 AC: 592 AN: 1111902

Other (OTH) AF: 0.000563 AC: 34 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152314 Hom.: 0 Cov.: 29 AF XY: 0.000322 AC XY: 24 AN XY: 74474

African (AFR) AF: 0.0000721 AC: 3 AN: 41596

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.108 Hom.: 756

Bravo AF: 0.000366

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000872

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;.;T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.4	M;M;.;.
PhyloP100		0.89
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.2	.;D;.;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.47
MVP		0.83
MPC		0.75
ClinPred		0.53	D
GERP RS		3.8
PromoterAI		0.088	Neutral
Varity_R		0.96
gMVP		0.56
Mutation Taster		=76/24	polymorphism

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;