4-109717607-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030821.5(PLA2G12A):c.392G>T(p.Cys131Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PLA2G12A NM_030821.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

PLA2G12A (HGNC:18554): (phospholipase A2 group XIIA) Secreted phospholipase A2 (sPLA2) enzymes liberate arachidonic acid from phospholipids for production of eicosanoids and exert a variety of physiologic and pathologic effects. Group XII sPLA2s, such as PLA2G12A, have relatively low specific activity and are structurally and functionally distinct from other sPLA2s (Gelb et al., 2000 [PubMed 11031251]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G12A	NM_030821.5	c.392G>T	p.Cys131Phe	missense_variant	3/4	ENST00000243501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G12A	ENST00000243501.10	c.392G>T	p.Cys131Phe	missense_variant	3/4	1	NM_030821.5	P3
PLA2G12A	ENST00000502283.1	c.386G>T	p.Cys129Phe	missense_variant	3/4	1		A1
PLA2G12A	ENST00000502772.1	n.186G>T		non_coding_transcript_exon_variant	2/2	5
PLA2G12A	ENST00000507961.1	c.*102G>T		3_prime_UTR_variant, NMD_transcript_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461518 Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000377 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.392G>T (p.C131F) alteration is located in exon 3 (coding exon 3) of the PLA2G12A gene. This alteration results from a G to T substitution at nucleotide position 392, causing the cysteine (C) at amino acid position 131 to be replaced by a phenylalanine (F). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.89		Loss of catalytic residue at L132 (P = 0.012);.;.;
MVP		0.67
MPC		0.32
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.94

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

Other links and lift over

dbSNP: rs1201429380; hg19: chr4-110638763;