13-30763972-A-G

Position:

• chr13-30763972-A-G

Variant summary

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

The NM_001629.4(ALOX5AP):​c.352A>G​(p.Ile118Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: ALOX5AP NM_001629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.17

Genes affected

ALOX5AP (HGNC:436): (arachidonate 5-lipoxygenase activating protein) This gene encodes a protein which, with 5-lipoxygenase, is required for leukotriene synthesis. Leukotrienes are arachidonic acid metabolites which have been implicated in various types of inflammatory responses, including asthma, arthritis and psoriasis. This protein localizes to the plasma membrane. Inhibitors of its function impede translocation of 5-lipoxygenase from the cytoplasm to the cell membrane and inhibit 5-lipoxygenase activation. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]

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=0.048710167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALOX5AP	NM_001629.4	c.352A>G	p.Ile118Val	missense_variant	5/5	ENST00000380490.5	NP_001620.2
ALOX5AP	NM_001204406.2	c.523A>G	p.Ile175Val	missense_variant	6/6		NP_001191335.1
ALOX5AP	XM_017020522.3	c.232A>G	p.Ile78Val	missense_variant	5/5		XP_016876011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALOX5AP	ENST00000380490.5	c.352A>G	p.Ile118Val	missense_variant	5/5	1	NM_001629.4	ENSP00000369858.3
ALOX5AP	ENST00000617770.4	c.523A>G	p.Ile175Val	missense_variant	6/6	1		ENSP00000479870.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251304 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.000242 AC XY: 176 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.523A>G (p.I175V) alteration is located in exon 6 (coding exon 6) of the ALOX5AP gene. This alteration results from a A to G substitution at nucleotide position 523, causing the isoleucine (I) at amino acid position 175 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ALOX5AP-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The ALOX5AP c.352A>G variant is predicted to result in the amino acid substitution p.Ile118Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0048	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.59	.;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.0	.;N
REVEL	Benign	0.067
Sift	Benign	0.50	.;T
Sift4G	Benign	0.35	T;T
Polyphen		0.047	.;B
Vest4		0.12
MVP		0.36
MPC		0.31
ClinPred		0.040	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.35

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: rs141412081; hg19: chr13-31338109;