6-46709361-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005084.4(PLA2G7):c.835G>T(p.Val279Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,607,748 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (378 hom.)
• Consequence: PLA2G7 NM_005084.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2 O:1
• Conservation: PhyloP100: 2.79

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022307456).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G7	NM_005084.4	c.835G>T	p.Val279Phe	missense_variant	9/12	ENST00000274793.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G7	ENST00000274793.12	c.835G>T	p.Val279Phe	missense_variant	9/12	1	NM_005084.4	P1
PLA2G7	ENST00000537365.1	c.835G>T	p.Val279Phe	missense_variant	9/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152092 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0726

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00455 AC: 1141 AN: 251010 Hom.: 40 AF XY: 0.00425 AC XY: 576 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0575

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00362 AC: 5270 AN: 1455538 Hom.: 378 Cov.: 27 AF XY: 0.00354 AC XY: 2562 AN XY: 724626

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.000860

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.0000976

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152210 Hom.: 21 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74418

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0726

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00249 Hom.: 17

Bravo AF: 0.00232

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00484 AC: 587

Asia WGS AF: 0.0300 AC: 105 AN: 3468

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Platelet-activating factor acetylhydrolase deficiency Pathogenic:1 Other:1

risk factor, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_005084.3:c.835G>T in the PLA2G7 gene has an allele frequency of 0.056 in East Asian subpopulation in the gnomAD database, including 41 homozygous occurrences. This variant has been reported as a genetic risk factor for stroke, asthma and cardiovascular disease (PMID: 9412624, 10194471, 16787988). Taken together, we interprete this variant as risk factor variant. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2006	- -

PLA2G7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2020

This variant is associated with the following publications: (PMID: 21834908, 19373214, 20080080, 20185515, 19034521, 9472966, 21606947, 21490708, 20926117, 16086290, 8675689, 11916011, 10194471, 9759612, 9412624, 16787988, 26595893, 26791069, 31589614, 11248283) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	0.000029	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.87
MVP		0.51
MPC		0.020
ClinPred		0.099	T
GERP RS		5.1
Varity_R		0.97
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76863441; hg19: chr6-46677098; COSMIC: COSV51264327;