6-46711495-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1BS2

The NM_005084.4(PLA2G7):c.663+1G>A variant causes a splice donor, intron 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, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2O: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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G7	NM_005084.4 link	c.663+1G>A		splice_donor_variant, intron_variant	Intron 7 of 11	ENST00000274793.12	NP_005075.3	Q13093

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G7	ENST00000274793.12 link	c.663+1G>A		splice_donor_variant, intron_variant	Intron 7 of 11	1	NM_005084.4	ENSP00000274793.7		Q13093
PLA2G7	ENST00000537365.1 link	c.663+1G>A		splice_donor_variant, intron_variant	Intron 7 of 11	1		ENSP00000445666.1		Q13093

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

GnomAD2 exomes

AF:

0.000963

AC:

242

AN:

251324

AF XY:

0.00120

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 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

AC:

AN:

33464

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44718

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26114

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39676

Gnomad4 SAS exome

AF:

0.00648

AC:

559

AN:

86248

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53406

Gnomad4 NFE exome

AF:

0.00000270

AC:

AN:

1111558

Gnomad4 Remaining exome

AF:

0.000745

AC:

AN:

60364

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000192976

AN:

0.000192976

Gnomad4 SAS

AF:

0.00912

AC:

0.00912484

AN:

0.00912484

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000151

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:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Platelet-activating factor acetylhydrolase deficiency

Pathogenic:1Other:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:curation

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. -

Jan 24, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

May 01, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PLA2G7-related disorder

Uncertain:1

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

GERP RS

4.7

Mutation Taster

=32/68

disease causing (ClinVar)

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