Variant 6-46711495-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_005084.4(PLA2G7):c.663+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000406 in 1,613,580 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 8 hom. )

Consequence

PLA2G7
NM_005084.4 splice_donor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 4.54

Variant links:

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]

PLA2G7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G7	NM_005084.4 linkuse as main transcript	c.663+1G>A		splice_donor_variant		ENST00000274793.12	NP_005075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G7	ENST00000274793.12 linkuse as main transcript	c.663+1G>A		splice_donor_variant		1	NM_005084.4	ENSP00000274793	P1
PLA2G7	ENST00000537365.1 linkuse as main transcript	c.663+1G>A		splice_donor_variant		1		ENSP00000445666	P1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000963

AC:

242

AN:

251324

Hom.:

AF XY:

0.00120

AC XY:

163

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00764

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000417

AC:

610

AN:

1461312

Hom.:

Cov.:

AF XY:

0.000596

AC XY:

433

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00648

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000296

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00912

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000287

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00111

AC:

135

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Platelet-activating factor acetylhydrolase deficiency

Pathogenic:1Other:1

risk factor, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_016204.1(NM_001168357.1):c.663+1G>A in the PLA2G7 gene has an allele frequency of 0.008 in South Asian subpopulation in the gnomAD database, including three homozygotes. The c.663+1G>A variant destroys the canonical splice donor site in intron 13. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. However, activity of soluble lipoprotein-associated phospholipase A2 (encoded by PLA2G7) has been correlated with risk for coronary heart disease (PMID: 28406212). Taken together, we interprete this variant as risk factor variant. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 24, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 01, 2022

Variant summary: PLA2G7 c.663+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00096 in 251324 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency does not allow conclusions about variant significance. c.663+1G>A has been reported in the literature in individuals affected with Lipoprotein-associated phospholipase A2 (Lp-PLA2) Deficiency, an enzyme that hydrolyzes phospholipids to generate lysophosphatidylcholine and oxidized nonesterified fatty acids (example, Salaheen_2017). In observational epidemiologic studies, higher soluble Lp-PLA2 enzymatic activity has been correlated with increased risk for coronary heart disease; small molecule inhibitors of Lp-PLA2 have been developed for the treatment of coronary heart disease (Salaheen_2017 citing Di Angelantonio_2012). This study identified participants who are naturally deficient in the Lp-PLA2 enzyme including two homozygotes and 106 heterozygotes. A dose-dependent response relationship between genotype and enzymatic activity was observed, however, carriers of c.663+1G>A did not have a reduced risk of myocardial infarction (Salaheen_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Platelet-Activating Factor Acetylhydrolase Deficiency and an associated risk for myocardial infarction and/or stroke. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014. The clinical diagnostic laboratory classified the variant as a risk factor for coronary heart disease citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.97

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

MutationTaster

Benign

1.0

D;D;D;D

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.76

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over