chr1-186870501-G-A

Position:

chr1-186870501-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024420.3(PLA2G4A):c.100G>A(p.Ala34Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,607,642 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PLA2G4A
NM_024420.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.90

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08790025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLA2G4A	NM_024420.3 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	3/18	ENST00000367466.4	NP_077734.2
PLA2G4A	NM_001311193.2 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	3/16		NP_001298122.2
PLA2G4A	XM_011509642.3 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	3/18		XP_011507944.1
PLA2G4A	XM_047422599.1 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	3/15		XP_047278555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G4A	ENST00000367466.4 linkuse as main transcript	c.100G>A	p.Ala34Thr	missense_variant	3/18	1	NM_024420.3	ENSP00000356436	P1
PLA2G4A	ENST00000466600.1 linkuse as main transcript	n.169G>A		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

250986

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000302

AC:

AN:

1455576

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724488

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000307

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 05, 2023	This variant has not been reported in the literature in individuals affected with PLA2G4A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the PLA2G4A protein (p.Ala34Thr). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.100G>A (p.A34T) alteration is located in exon 3 (coding exon 2) of the PLA2G4A gene. This alteration results from a G to A substitution at nucleotide position 100, causing the alanine (A) at amino acid position 34 to be replaced by a threonine (T). 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

0.089

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.19

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.82

M_CAP

Benign

0.0073

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.92

MutationTaster

Benign

0.56

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.010

REVEL

Benign

0.028

Sift

Benign

0.60

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.15

MutPred

0.36

Loss of catalytic residue at A34 (P = 0.0205);

MVP

0.77

MPC

0.52

ClinPred

0.034

GERP RS

3.3

Varity_R

0.063

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over