6-46704609-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005084.4(PLA2G7):c.1277A>G(p.Asn426Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,589,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PLA2G7 NM_005084.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.729

Genes affected

PLA2G7 (HGNC:9040): (phospholipase A2 group VII) The protein encoded by this gene is a secreted enzyme that catalyzes the degradation of platelet-activating factor to biologically inactive products. Defects in this gene are a cause of platelet-activating factor acetylhydrolase deficiency. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006942719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G7	NM_005084.4	c.1277A>G	p.Asn426Ser	missense_variant	12/12	ENST00000274793.12
PLA2G7	NM_001168357.2	c.1277A>G	p.Asn426Ser	missense_variant	12/12
PLA2G7	XM_005249408.5	c.1277A>G	p.Asn426Ser	missense_variant	12/12
PLA2G7	XM_047419359.1	c.1142A>G	p.Asn381Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G7	ENST00000274793.12	c.1277A>G	p.Asn426Ser	missense_variant	12/12	1	NM_005084.4	P1
PLA2G7	ENST00000537365.1	c.1277A>G	p.Asn426Ser	missense_variant	12/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152082 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000386 AC: 97 AN: 251094 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135726

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000138 AC: 198 AN: 1437658 Hom.: 0 Cov.: 28 AF XY: 0.000114 AC XY: 82 AN XY: 716966

Gnomad4 AFR exome AF: 0.00417

Gnomad4 AMR exome AF: 0.000560

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: 0.00000826

Gnomad4 OTH exome AF: 0.000403

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152200 Hom.: 1 Cov.: 31 AF XY: 0.00121 AC XY: 90 AN XY: 74436

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.00170

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000437 AC: 53

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 19, 2023

Variant summary: PLA2G7 c.1277A>G (p.Asn426Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 282482 control chromosomes in the gnomAD database, including 1 homozygotes sgeesting a benign role for this variant. To our knowledge, no occurrence of c.1277A>G in individuals affected with Platelet-Activating Factor Acetylhydrolase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.35
Dann	Benign	0.56
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.057	N
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.047
Sift	Benign	0.57	T;T
Sift4G	Benign	0.99	T;T
Polyphen		0.0010	B;B
Vest4		0.047
MVP		0.24
MPC		0.0054
ClinPred		0.0072	T
GERP RS		-0.40
Varity_R		0.052
gMVP		0.13

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: rs140268311; hg19: chr6-46672346;