1-19978510-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001395463.1(PLA2G2A):c.55C>T(p.His19Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,613,646 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0065 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (107 hom.)
• Consequence: PLA2G2A NM_001395463.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.463

Genes affected

PLA2G2A (HGNC:9031): (phospholipase A2 group IIA) The protein encoded by this gene is a member of the phospholipase A2 family (PLA2). PLA2s constitute a diverse family of enzymes with respect to sequence, function, localization, and divalent cation requirements. This gene product belongs to group II, which contains secreted form of PLA2, an extracellular enzyme that has a low molecular mass and requires calcium ions for catalysis. It catalyzes the hydrolysis of the sn-2 fatty acid acyl ester bond of phosphoglycerides, releasing free fatty acids and lysophospholipids, and thought to participate in the regulation of the phospholipid metabolism in biomembranes. Several alternatively spliced transcript variants with different 5' UTRs have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006665617).
• BP6: Variant 1-19978510-G-A is Benign according to our data. Variant chr1-19978510-G-A is described in ClinVar as [Benign]. Clinvar id is 712953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00645 (983/152302) while in subpopulation EAS AF= 0.0332 (172/5180). AF 95% confidence interval is 0.0292. There are 20 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G2A	NM_001395463.1	c.55C>T	p.His19Tyr	missense_variant	3/5	ENST00000482011.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G2A	ENST00000482011.3	c.55C>T	p.His19Tyr	missense_variant	3/5	1	NM_001395463.1	P1

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 979 AN: 152184 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.0106 AC: 2657 AN: 251110 Hom.: 47 AF XY: 0.00969 AC XY: 1315 AN XY: 135750

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0288

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.00312

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00434 AC: 6343 AN: 1461344 Hom.: 107 Cov.: 36 AF XY: 0.00409 AC XY: 2976 AN XY: 726988

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.0351

Gnomad4 SAS exome AF: 0.000927

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.00645 AC: 983 AN: 152302 Hom.: 20 Cov.: 33 AF XY: 0.00835 AC XY: 622 AN XY: 74460

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00297 Hom.: 15

Bravo AF: 0.00372

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00937 AC: 1138

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PLA2G2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 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

Invitae

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	9.5
Dann	Benign	0.94
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.22	T;.
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.016
Sift	Benign	0.11	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0040	B;B
Vest4		0.18
MPC		0.60
ClinPred		0.0022	T
GERP RS		2.9
Varity_R		0.094
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11573162; hg19: chr1-20305003; COSMIC: COSV64286982;