17-4631891-T-C

Position:

• chr17-4631891-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001140.5(ALOX15):​c.1807A>G​(p.Met603Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,611,296 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: ALOX15 NM_001140.5 missense, splice_region
• Scores: Splicing: ADA: 0.009887
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.25

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017335206).
• BP6: Variant 17-4631891-T-C is Benign according to our data. Variant chr17-4631891-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 717665.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOX15	NM_001140.5	c.1807A>G	p.Met603Val	missense_variant, splice_region_variant	13/14	ENST00000293761.8	NP_001131.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOX15	ENST00000293761.8	c.1807A>G	p.Met603Val	missense_variant, splice_region_variant	13/14	1	NM_001140.5	ENSP00000293761	P1
ALOX15	ENST00000570836.6	c.1807A>G	p.Met603Val	missense_variant, splice_region_variant	14/15	2		ENSP00000458832	P1
ALOX15	ENST00000574640.1	c.1690A>G	p.Met564Val	missense_variant, splice_region_variant	13/14	2		ENSP00000460483

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00152 AC: 377 AN: 248486 Hom.: 1 AF XY: 0.00150 AC XY: 201 AN XY: 134216

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.000715

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00100

Gnomad FIN exome AF: 0.000796

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00171 AC: 2502 AN: 1458976 Hom.: 3 Cov.: 33 AF XY: 0.00173 AC XY: 1252 AN XY: 725454

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000810

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.000902

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74504

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.00146

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00142 AC: 172

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Uncertain	0.44	T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.66	.;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	0.92	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	.;N;.
REVEL	Benign	0.29
Sift	Benign	0.13	.;T;.
Sift4G	Benign	0.082	T;T;T
Polyphen		0.067	B;B;.
Vest4		0.31
MVP		0.69
MPC		0.20
ClinPred		0.021	T
GERP RS		3.2
Varity_R		0.22
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0099
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.14		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: rs138472652; hg19: chr17-4535186;