6-46711495-C-T

Variant names:

• chr6-46711495-C-T
• rs201899866
• NM_005084.4:c.663+1G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP3 BS2

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, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 5 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.
• 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 rank	MANE	Protein	UniProt
PLA2G7	NM_005084.4	c.663+1G>A		splice_donor_variant, intron_variant	Intron 7 of 11	ENST00000274793.12	NP_005075.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152150 Hom.: 0 Cov.: 32

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.: 3 AF XY: 0.00120 AC XY: 163 AN XY: 135838

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.: 8 Cov.: 31 AF XY: 0.000596 AC XY: 433 AN XY: 726968

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: 45 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74456

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.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00111 AC: 135

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 24, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.97
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	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

Other links and lift over

dbSNP: rs201899866; hg19: chr6-46679232;