chr1-186893060-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024420.3(PLA2G4A):​c.165C>G​(p.Asp55Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLA2G4A
NM_024420.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0460

Publications

0 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.102580965).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLA2G4ANM_024420.3 linkc.165C>G p.Asp55Glu missense_variant Exon 4 of 18 ENST00000367466.4 NP_077734.2 P47712

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLA2G4AENST00000367466.4 linkc.165C>G p.Asp55Glu missense_variant Exon 4 of 18 1 NM_024420.3 ENSP00000356436.3 P47712
PLA2G4AENST00000466600.1 linkn.234C>G non_coding_transcript_exon_variant Exon 3 of 7 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456724
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
725078
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33368
American (AMR)
AF:
0.0000224
AC:
1
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39642
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86166
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1107354
Other (OTH)
AF:
0.00
AC:
0
AN:
60218
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLA2G4A protein function. 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. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 55 of the PLA2G4A protein (p.Asp55Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLA2G4A-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
13
DANN
Benign
0.83
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.45
N
PhyloP100
0.046
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.32
N
REVEL
Benign
0.16
Sift
Benign
0.52
T
Sift4G
Benign
0.56
T
Polyphen
0.0
B
Vest4
0.18
MutPred
0.28
Gain of sheet (P = 0.0827);
MVP
0.71
MPC
0.51
ClinPred
0.24
T
GERP RS
1.2
Varity_R
0.31
gMVP
0.62
Mutation Taster
=68/32
polymorphism

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

Other links and lift over

dbSNP: rs1200427496; hg19: chr1-186862192; API