17-4633168-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001140.5(ALOX15):c.1396C>T(p.Arg466Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: ALOX15 NM_001140.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0960

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075189054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOX15	NM_001140.5	c.1396C>T	p.Arg466Trp	missense_variant	10/14	ENST00000293761.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOX15	ENST00000293761.8	c.1396C>T	p.Arg466Trp	missense_variant	10/14	1	NM_001140.5	P1
ALOX15	ENST00000570836.6	c.1396C>T	p.Arg466Trp	missense_variant	11/15	2		P1
ALOX15	ENST00000574640.1	c.1279C>T	p.Arg427Trp	missense_variant	10/14	2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251064 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135758

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 727188

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74434

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1396C>T (p.R466W) alteration is located in exon 10 (coding exon 10) of the ALOX15 gene. This alteration results from a C to T substitution at nucleotide position 1396, causing the arginine (R) at amino acid position 466 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.43	T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.71	P;P;.
Vest4		0.54
MVP		0.89
MPC		0.24
ClinPred		0.13	T
GERP RS		1.4
Varity_R		0.66
gMVP		0.40

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: rs144526853; hg19: chr17-4536463; COSMIC: COSV53396100; COSMIC: COSV53396100;