10-45412248-T-A

Variant names:

• chr10-45412248-T-A
• NM_000698.5:c.489T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000698.5(ALOX5):​c.489T>A​(p.Asp163Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALOX5 NM_000698.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.212

Genes affected

ALOX5 (HGNC:435): (arachidonate 5-lipoxygenase) This gene encodes a member of the lipoxygenase gene family and plays a dual role in the synthesis of leukotrienes from arachidonic acid. The encoded protein, which is expressed specifically in bone marrow-derived cells, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid, and further to the allylic epoxide 5(S)-trans-7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). Leukotrienes are important mediators of a number of inflammatory and allergic conditions. Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05201122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALOX5	NM_000698.5	c.489T>A	p.Asp163Glu	missense_variant	Exon 4 of 14	ENST00000374391.7	NP_000689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALOX5	ENST00000374391.7	c.489T>A	p.Asp163Glu	missense_variant	Exon 4 of 14	1	NM_000698.5	ENSP00000363512.2
ALOX5	ENST00000542434.5	c.489T>A	p.Asp163Glu	missense_variant	Exon 4 of 13	1		ENSP00000437634.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.489T>A (p.D163E) alteration is located in exon 4 (coding exon 4) of the ALOX5 gene. This alteration results from a T to A substitution at nucleotide position 489, causing the aspartic acid (D) at amino acid position 163 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.29	.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.28	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.14
Sift	Benign	0.72	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0010	.;B
Vest4		0.15
MutPred		0.42		Gain of ubiquitination at K162 (P = 0.0773);Gain of ubiquitination at K162 (P = 0.0773);
MVP		0.59
MPC		0.27
ClinPred		0.087	T
GERP RS		1.3
Varity_R		0.073
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-45907696;