rs201801144

Positions:

chr22-38126390-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003560.4(PLA2G6):c.1408A>G(p.Met470Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,613,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 0.0990

Variant links:

Genes affected

PLA2G6 (HGNC:9039): (phospholipase A2 group VI) The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]

PLA2G6 links:

PLA2G6 (HGNC:):

PLA2G6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029822022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1408A>G	p.Met470Val	missense_variant	10/17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.1408A>G	p.Met470Val	missense_variant	10/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000498

AC:

125

AN:

251100

Hom.:

AF XY:

0.000589

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000714

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000463

AC:

677

AN:

1461330

Hom.:

Cov.:

AF XY:

0.000475

AC XY:

345

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00106

Gnomad4 FIN exome

AF:

0.0000940

Gnomad4 NFE exome

AF:

0.000496

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000348

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000507

Hom.:

Bravo

AF:

0.000306

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2023	Reported in a patient with infantile neuroaxonal dystrophy who harbored a second PLA2G6 variant on the opposite allele (Arslan et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 29618726, 27467583, 34272103, 31493945, 29118384) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PLA2G6: PS4:Supporting, BP4 -

Infantile neuroaxonal dystrophy

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PLA2G6 related disorder (PMID:31493945, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.888, PP3_P). A missense variant is a common mechanism associated with Infantile neuroaxonal dystrophy 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000485, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2022

The c.1408A>G (p.M470V) alteration is located in exon 10 (coding exon 9) of the PLA2G6 gene. This alteration results from a A to G substitution at nucleotide position 1408, causing the methionine (M) at amino acid position 470 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.8

DANN

Benign

0.45

DEOGEN2

Benign

0.083

T;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.82

T;T;.

M_CAP

Benign

0.017

MetaRNN

Benign

0.030

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.72

N;N;N

REVEL

Benign

0.092

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.34

MVP

0.49

MPC

0.25

ClinPred

0.012

GERP RS

1.5

Varity_R

0.044

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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