17-4638309-C-T

Variant names:

• chr17-4638309-C-T
• rs3892408
• NM_001140.5:c.715G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001140.5(ALOX15):​c.715G>A​(p.Val239Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (0 hom., cov: 20)
  • Exomes 𝑓: 0.028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALOX15 NM_001140.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230
• Publications: 6 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056161582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX15	NM_001140.5	c.715G>A	p.Val239Met	missense_variant	Exon 6 of 14	ENST00000293761.8	NP_001131.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX15	ENST00000293761.8	c.715G>A	p.Val239Met	missense_variant	Exon 6 of 14	1	NM_001140.5	ENSP00000293761.3
ALOX15	ENST00000570836.6	c.715G>A	p.Val239Met	missense_variant	Exon 7 of 15	2		ENSP00000458832.1
ALOX15	ENST00000574640.1	c.598G>A	p.Val200Met	missense_variant	Exon 6 of 14	2		ENSP00000460483.1
ALOX15	ENST00000576572.1	n.306G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.194 AC: 16008 AN: 82538 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.00293 AC: 262 AN: 89316 AF XY: 0.00240

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.000588

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00195

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00282

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0280 AC: 12590 AN: 449222 Hom.: 0 Cov.: 8 AF XY: 0.0262 AC XY: 6157 AN XY: 235064

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

African (AFR) AF: 0.0343 AC: 449 AN: 13088

American (AMR) AF: 0.0154 AC: 356 AN: 23184

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 294 AN: 11932

East Asian (EAS) AF: 0.0872 AC: 1508 AN: 17300

South Asian (SAS) AF: 0.00395 AC: 182 AN: 46120

European-Finnish (FIN) AF: 0.0377 AC: 1002 AN: 26604

Middle Eastern (MID) AF: 0.0297 AC: 50 AN: 1686

European-Non Finnish (NFE) AF: 0.0280 AC: 8031 AN: 286984

Other (OTH) AF: 0.0322 AC: 718 AN: 22324

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.194 AC: 16011 AN: 82612 Hom.: 0 Cov.: 20 AF XY: 0.194 AC XY: 7845 AN XY: 40394

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

African (AFR) AF: 0.249 AC: 5347 AN: 21444

American (AMR) AF: 0.235 AC: 1905 AN: 8118

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 255 AN: 2040

East Asian (EAS) AF: 0.308 AC: 830 AN: 2692

South Asian (SAS) AF: 0.219 AC: 559 AN: 2556

European-Finnish (FIN) AF: 0.152 AC: 926 AN: 6096

Middle Eastern (MID) AF: 0.199 AC: 31 AN: 156

European-Non Finnish (NFE) AF: 0.154 AC: 5839 AN: 37900

Other (OTH) AF: 0.182 AC: 208 AN: 1142

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0469 Hom.: 0

ExAC AF: 0.00233 AC: 116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.2
DANN	Benign	0.080
DEOGEN2	Benign	0.17	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.64	.;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.60	N;N;.
PhyloP100		0.23
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	1.4	.;N;.
REVEL	Benign	0.012
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.095
MVP		0.18
MPC		0.18
ClinPred		0.00061	T
GERP RS		3.0
Varity_R		0.058
gMVP		0.13
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3892408; hg19: chr17-4541604; COSMIC: COSV53396176; COSMIC: COSV53396176;