Genetic Variant ALOX15:c.-272G>A (chr17-4641923-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000574640.1(ALOX15):c.-272G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 534,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

ALOX15
ENST00000574640.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.886

Publications

8 publications found

Variant links:

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

ALOX15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX15	NM_001140.5 link	c.-272G>A		upstream_gene_variant		ENST00000293761.8	NP_001131.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ALOX15	ENST00000574640.1 link	c.-272G>A	5_prime_UTR_variant	Exon 1 of 14	2		ENSP00000460483.1
ALOX15	ENST00000570836.6 link	c.-25-247G>A	intron_variant	Intron 1 of 14	2		ENSP00000458832.1
ALOX15	ENST00000293761.8 link	c.-272G>A	upstream_gene_variant		1	NM_001140.5	ENSP00000293761.3
ALOX15	ENST00000573740.1 link	n.-245G>A	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD4 exome

AF:

0.00000785

AC:

AN:

382208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

201580

show subpopulations

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

African (AFR)

AF:

0.0000914

AC:

AN:

10938

American (AMR)

AF:

0.00

AC:

AN:

16148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11500

East Asian (EAS)

AF:

0.00

AC:

AN:

24246

South Asian (SAS)

AF:

0.00

AC:

AN:

43722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1644

European-Non Finnish (NFE)

AF:

0.00000434

AC:

AN:

230366

Other (OTH)

AF:

0.0000459

AC:

AN:

21802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151854

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74122

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

1193

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.5

(source)

DANN

Benign

0.74

PhyloP100

-0.89

PromoterAI

-0.0041

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over