rs199935023

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_003560.4(PLA2G6):c.991G>T(p.Asp331Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,557,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D331N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.36

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003560.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-38132917-C-A is Pathogenic according to our data. Variant chr22-38132917-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 30371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38132917-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.991G>T	p.Asp331Tyr	missense_variant	7/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.991G>T	p.Asp331Tyr	missense_variant	7/17	1	NM_003560.4	P3	O60733-1
	ENST00000624072.1 linkuse as main transcript	n.2702C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152258

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:

0.000769

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000486

AC:

AN:

164594

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

87358

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000660

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1404778

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

693754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000414

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000515

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000172

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile neuroaxonal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 331 of the PLA2G6 protein (p.Asp331Tyr). This variant is present in population databases (rs199935023, gnomAD 0.08%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 21700586, 22213678, 25660576). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30371). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLA2G6 protein function. Experimental studies have shown that this missense change affects PLA2G6 function (PMID: 21700586). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive Parkinson disease 14

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 05, 2011

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21700586, 25660576, 22213678, 29454663, 30302010, 31196701, 30772976, 31496990, 32183746, 30088174, 32961396) -

PLA2G6-associated neurodegeneration

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The p.Asp331Tyr variant in PLA2G6 has been reported in at least 4 individuals with PLA2G6-associated neurodegeneration (PMID: 29454663, 31196701, 22213678) and has been identified in 0.08% (11/13680) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs199935023). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 30371) and has been interpreted as pathogenic by GeneDx and OMIM. Of the 4 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans and 2 of those were homozygotes, which increases the likelihood that the p.Asp331Tyr variant is pathogenic (Variant ID: 279875; PMID: 29454663, 31196701, 22213678). In vitro functional studies provide some evidence that the p.Asp331Tyr variant may slightly impact protein function (PMID: 21700586). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes PLA2G6-associated neurodegeneration (PMID: 30088174). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3_strong, PS3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Pathogenic

0.20

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.2

M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.67

P;D;D

Vest4

0.90

MVP

0.88

MPC

0.96

ClinPred

0.86

GERP RS

5.5

Varity_R

0.69

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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