chr19-48062095-C-G

Variant names:

• chr19-48062095-C-G
• rs201127134
• NM_003706.3:c.1160G>C
• PLA2G4C p.Gly387Ala

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Moderate

The NM_003706.3(PLA2G4C):c.1160G>C (p.Gly387Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000348 (AC=56) in the gnomAD database across 1,611,200 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000121. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G387S: Uncertain_significance (ClinVar VariationId 4138261, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (1 hom.)
• Consequence: PLA2G4C NM_003706.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• Publications: 1 publications found

Genes affected

PLA2G4C (HGNC:9037): (phospholipase A2 group IVC) This gene encodes a protein which is a member of the phospholipase A2 enzyme family which hydrolyzes glycerophospholipids to produce free fatty acids and lysophospholipids, both of which serve as precursors in the production of signaling molecules. The encoded protein has been shown to be a calcium-independent and membrane bound enzyme. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2009]

PLA2G4C-AS1 (HGNC:51585): (PLA2G4C antisense RNA 1)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000121 — borderline rare for unknown gene (threshold 0.001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003706.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G4C	NM_003706.3	MANE Select	c.1160G>C	p.Gly387Ala	missense	Exon 14 of 17	NP_003697.2	Q9UP65-1
	PLA2G4C	NM_001159322.2		c.1190G>C	p.Gly397Ala	missense	Exon 14 of 17	NP_001152794.1	Q9UP65-3
	PLA2G4C	NM_001159323.2		c.1160G>C	p.Gly387Ala	missense	Exon 14 of 17	NP_001152795.1	Q9UP65-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G4C	ENST00000599921.6	TSL:1 MANE Select	c.1160G>C	p.Gly387Ala	missense	Exon 14 of 17	ENSP00000469473.1	Q9UP65-1
	PLA2G4C	ENST00000595161.5	TSL:3	c.224G>C	p.Gly75Ala	missense	Exon 3 of 5	ENSP00000469528.1	M0QY18
	PLA2G4C	ENST00000887096.1		c.1217G>C	p.Gly406Ala	missense	Exon 15 of 18	ENSP00000557155.1	A0ACI8QRI2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152162	Cov:32
GnomAD2 exomes	AF: 0.0000525	AC:13	Hom:	AN:247794	Cov:
GnomAD4 exome	AF: 0.0000350	AC:51	Hom:1	AN:1459038	Cov:31
GnomAD4 genome	AF: 0.0000329	AC:5	Hom:0	AN:152162	Cov:32
TOPMed (Bravo)	AF: 0.0000831	AC:22	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000548	AC:5	Hom:0	AN:91262	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Turkish Variome	AF: 0.000744	AC:5	Hom:0	AN:6720	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000954	4	41946	0.0000449	3	66816
SCHEMA(Schizophrenia)	0.000151	17	112546	0.0000794	15	189028

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.026
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.31	N
FuncVEP CTI	Pathogenic	0.64
GPN-Star LLR	N/A	-0.24
GPN-Star score	N/A	0.24
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	85/15	polymorphism
MutationAssessor	Uncertain	2.3	M
PhyloP100	Benign	1.6
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Varity_R	N/A	0.48
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201127134;

hg19: chr19-48565352;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar