chr19-48053000-G-T

Variant names:

• chr19-48053000-G-T
• rs780130778
• NM_003706.3:c.1577C>A
• PLA2G4C p.Ala526Asp

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-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). PM2BP4

The NM_003706.3(PLA2G4C):c.1577C>A (p.Ala526Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000206 (AC=3) in the gnomAD database across 1,454,596 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLA2G4C NM_003706.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.161
• Publications: 0 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]

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 1 points.

• PM2: Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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.1577C>A	p.Ala526Asp	missense	Exon 16 of 17	NP_003697.2	Q9UP65-1
	PLA2G4C	NM_001159322.2		c.1607C>A	p.Ala536Asp	missense	Exon 16 of 17	NP_001152794.1	Q9UP65-3
	PLA2G4C	NM_001159323.2		c.1577C>A	p.Ala526Asp	missense	Exon 16 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.1577C>A	p.Ala526Asp	missense	Exon 16 of 17	ENSP00000469473.1	Q9UP65-1
	PLA2G4C	ENST00000594790.1	TSL:1	n.330C>A		non_coding_transcript_exon	Exon 2 of 3
	PLA2G4C	ENST00000887096.1		c.1634C>A	p.Ala545Asp	missense	Exon 17 of 18	ENSP00000557155.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249202 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454596 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722370

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106726

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.16
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.010	D
Varity_R		0.29
gMVP		0.71
Mutation Taster		=100/0	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

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

Other links and lift over

dbSNP: rs780130778;

hg19: chr19-48556257;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar