rs4650708

Variant names:

• chr1-186940985-A-C
• rs4650708
• NM_024420.3:c.1033+891A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024420.3(PLA2G4A):​c.1033+891A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 151,864 control chromosomes in the GnomAD database, including 5,382 homozygotes. 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 0.25 (5382 hom., cov: 31)
• Consequence: PLA2G4A NM_024420.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.722
• Publications: 3 publications found

Genes affected

PLA2G4A (HGNC:9035): (phospholipase A2 group IVA) This gene encodes a member of the cytosolic phospholipase A2 group IV family. The enzyme catalyzes the hydrolysis of membrane phospholipids to release arachidonic acid which is subsequently metabolized into eicosanoids. Eicosanoids, including prostaglandins and leukotrienes, are lipid-based cellular hormones that regulate hemodynamics, inflammatory responses, and other intracellular pathways. The hydrolysis reaction also produces lysophospholipids that are converted into platelet-activating factor. The enzyme is activated by increased intracellular Ca(2+) levels and phosphorylation, resulting in its translocation from the cytosol and nucleus to perinuclear membrane vesicles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

PLA2G4A Gene-Disease associations (from GenCC):

• cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• cryptogenic multifocal ulcerous stenosing enteritis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G4A	NM_024420.3	c.1033+891A>C		intron_variant	Intron 10 of 17	ENST00000367466.4	NP_077734.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G4A	ENST00000367466.4	c.1033+891A>C		intron_variant	Intron 10 of 17	1	NM_024420.3	ENSP00000356436.3

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38461 AN: 151746 Hom.: 5368 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.273

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.254 AC: 38503 AN: 151864 Hom.: 5382 Cov.: 31 AF XY: 0.256 AC XY: 19023 AN XY: 74246

African (AFR) AF: 0.178 AC: 7391 AN: 41412

American (AMR) AF: 0.401 AC: 6118 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3462

East Asian (EAS) AF: 0.159 AC: 819 AN: 5150

South Asian (SAS) AF: 0.341 AC: 1641 AN: 4814

European-Finnish (FIN) AF: 0.258 AC: 2724 AN: 10542

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18267 AN: 67924

Other (OTH) AF: 0.272 AC: 574 AN: 2112

Alfa AF: 0.261 Hom.: 707

Bravo AF: 0.262

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.1
DANN	Benign	0.83
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4650708; hg19: chr1-186910117; COSMIC: COSV66557294; COSMIC: COSV66557294;