Genetic Variant NM_001395463.1:c.55C>T (chr1-19978510-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 20 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 107 hom. )

Consequence

PLA2G2A
NM_001395463.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.463

Publications

11 publications found

Variant links:

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]

PLA2G2A Gene-Disease associations (from GenCC):

colorectal cancer
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

PLA2G2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 983 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395463.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLA2G2A	NM_001395463.1	MANE Select	c.55C>T	p.His19Tyr	missense	Exon 3 of 5	NP_001382392.1	P14555
PLA2G2A	NM_000300.4		c.55C>T	p.His19Tyr	missense	Exon 4 of 6	NP_000291.1	P14555
PLA2G2A	NM_001161727.2		c.55C>T	p.His19Tyr	missense	Exon 4 of 6	NP_001155199.1	P14555

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLA2G2A	ENST00000482011.3	TSL:1 MANE Select	c.55C>T	p.His19Tyr	missense	Exon 3 of 5	ENSP00000504762.1	P14555
PLA2G2A	ENST00000375111.7	TSL:1	c.55C>T	p.His19Tyr	missense	Exon 4 of 6	ENSP00000364252.3	P14555
PLA2G2A	ENST00000400520.8	TSL:1	c.55C>T	p.His19Tyr	missense	Exon 3 of 5	ENSP00000383364.3	P14555

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

979

AN:

152184

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0106

AC:

2657

AN:

251110

AF XY:

0.00969

show subpopulations

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 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.:

AF XY:

0.00409

AC XY:

2976

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33478

American (AMR)

AF:

0.0175

AC:

783

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

26136

East Asian (EAS)

AF:

0.0351

AC:

1395

AN:

39700

South Asian (SAS)

AF:

0.000927

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0471

AC:

2496

AN:

52960

Middle Eastern (MID)

AF:

0.00158

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00109

AC:

1209

AN:

1111998

Other (OTH)

AF:

0.00493

AC:

298

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

380

761

1141

1522

1902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00645

AC:

983

AN:

152302

Hom.:

Cov.:

AF XY:

0.00835

AC XY:

622

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41582

American (AMR)

AF:

0.00830

AC:

127

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.0332

AC:

172

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0475

AC:

504

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00198

AC:

135

AN:

68014

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00348

Hom.:

Bravo

AF:

0.00372

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00937

AC:

1138

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

PLA2G2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.5

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.35

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.46

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

REVEL

Benign

0.016

Sift

Benign

0.11

Sift4G

Benign

0.17

Polyphen

0.0040

Vest4

0.18

MPC

0.60

ClinPred

0.0022

GERP RS

2.9

Varity_R

0.094

gMVP

0.49

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over