rs535486098

chr22-38120888-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_003560.4(PLA2G6):c.1613G>A(p.Arg538His) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R538C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003560.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-38120889-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 809367.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

PP5

Variant 22-38120888-C-T is Pathogenic according to our data. Variant chr22-38120888-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1613G>A	p.Arg538His	missense_variant	12/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.1613G>A	p.Arg538His	missense_variant	12/17	1	NM_003560.4	P3	O60733-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251146

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461332

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000371

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

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

Oct 22, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the PLA2G6 protein (p.Arg538His). This variant is present in population databases (rs535486098, gnomAD 0.006%). This missense change has been observed in individuals with infantile neuroaxonal dystrophy and/or Parkinson disease (PMID: 27146152, 27196560, 32771225). ClinVar contains an entry for this variant (Variation ID: 159739). 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. This variant disrupts the p.Arg538Cys amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16783378, 24252552, 32771225; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Iron accumulation in brain

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146152, 27196560, 33144682, 32771225) -

PLA2G6-associated neurodegeneration

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 24, 2023

The p.Arg538His variant in PLA2G6 has been reported in 5 individuals with PLA2G6-associated neurodegeneration (PMID: 27196560, 27146152, 33144682, Agarwal_2020, 32771225), segregated with disease in 2 affected relatives from 2 families (Agarwal_2020) and has been identified in 0.007% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs535486098). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 159739) and has been interpreted as pathogenic or likely pathogenic by Genetic Services Laboratory (University of Chicago), Neuberg Supratech Reference Laboratories Pvt Ltd (Neuberg Centre for Genomic Medicine), GeneDx, and Invitae. Of the 5 affected individuals, 4 of those were homozygotes, which increases the likelihood that the p.Arg538His variant is pathogenic (PMID: 27196560, 27146152, 33144682, Agarwal_2020). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual homozygous for this variant is highly specific for PLA2G6-associated neurodegeneration based on brain iron accumulation on MRI consistent with disease (PMID: 27196560). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM2, PM3, PP1, PP4 (Richards 2015). -

Neurodegeneration with brain iron accumulation 2B

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant p.R538H in PLA2G6 (NM_003560.4) has been reported previously in individuals with infantile neuroaxonal dystrophy (INAD) (Megahed et al, 2016; Kapoor et al, 2016). It has been submitted to the ClinVar database as Pathogenic. Another missense affecting the same amino acid has also been reported to be disease causing (Morgan T et al, 2006). The p.R538H variant is observed in 2/30,616 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. The p.R538H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 538 of PLA2G6 is conserved in all mammalian species. The nucleotide c.1613 in PLA2G6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.080

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;D;.

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.7

M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.044

D;D;D

Sift4G

Benign

0.19

T;T;T

Polyphen

0.89

P;D;D

Vest4

0.95

MutPred

0.61

Loss of helix (P = 0.0093);.;.;

MVP

0.93

MPC

0.89

ClinPred

0.89

GERP RS

5.5

Varity_R

0.39

gMVP

0.77

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