chr1-186870519-A-AAG

Variant names:

• chr1-186870519-A-AAG
• rs757481718
• NM_024420.3:c.115+4_115+5dupAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024420.3(PLA2G4A):​c.115+4_115+5dupAG variant causes a splice region, intron change. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLA2G4A NM_024420.3 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.48
• Publications: 0 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), Ambry Genetics, Orphanet, ClinGen
• cryptogenic multifocal ulcerous stenosing enteritis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G4A	NM_024420.3	MANE Select	c.115+4_115+5dupAG		splice_region intron	N/A	NP_077734.2	P47712
	PLA2G4A	NM_001311193.2		c.115+4_115+5dupAG		splice_region intron	N/A	NP_001298122.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G4A	ENST00000367466.4	TSL:1 MANE Select	c.115+3_115+4insAG		splice_region intron	N/A	ENSP00000356436.3	P47712
	PLA2G4A	ENST00000851114.1		c.115+3_115+4insAG		splice_region intron	N/A	ENSP00000521173.1
	PLA2G4A	ENST00000851115.1		c.115+3_115+4insAG		splice_region intron	N/A	ENSP00000521174.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 77 AN: 148470 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000348

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.000470

Gnomad ASJ AF: 0.000582

Gnomad EAS AF: 0.000793

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.00230

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000284

Gnomad OTH AF: 0.000978

GnomAD2 exomes AF: 0.0000440 AC: 11 AN: 250162 AF XY: 0.0000666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000471 AC: 68 AN: 1442954 Hom.: 0 Cov.: 27 AF XY: 0.0000543 AC XY: 39 AN XY: 718888

African (AFR) AF: 0.00 AC: 0 AN: 33060

American (AMR) AF: 0.000112 AC: 5 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25972

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39556

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85806

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53356

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.0000438 AC: 48 AN: 1095212

Other (OTH) AF: 0.0000503 AC: 3 AN: 59700

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000518 AC: 77 AN: 148570 Hom.: 0 Cov.: 32 AF XY: 0.000482 AC XY: 35 AN XY: 72646

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

African (AFR) AF: 0.000372 AC: 15 AN: 40354

American (AMR) AF: 0.000402 AC: 6 AN: 14924

Ashkenazi Jewish (ASJ) AF: 0.000582 AC: 2 AN: 3438

East Asian (EAS) AF: 0.000795 AC: 4 AN: 5030

South Asian (SAS) AF: 0.00129 AC: 6 AN: 4658

European-Finnish (FIN) AF: 0.00230 AC: 23 AN: 9984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000284 AC: 19 AN: 66948

Other (OTH) AF: 0.000484 AC: 1 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00166 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=18/82	disease causing

Splicing

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

Other links and lift over

dbSNP: rs757481718; hg19: chr1-186839651;