rs121908681

Positions:

Variant summary

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

The ENST00000332509.8(PLA2G6):c.1634A>G(p.Lys545Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,532 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. K545T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PLA2G6
ENST00000332509.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.25

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 ENST00000332509.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-38120867-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

PP5

Variant 22-38120867-T-C is Pathogenic according to our data. Variant chr22-38120867-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1634A>G	p.Lys545Arg	missense_variant	12/17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.1634A>G	p.Lys545Arg	missense_variant	12/17	1	NM_003560.4	ENSP00000333142	P3	O60733-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251320

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

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:

0.00000684

AC:

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 03, 2023

Variant summary: PLA2G6 c.1634A>G (p.Lys545Arg) results in a conservative amino acid change located in the patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251320 control chromosomes (gnomAD). c.1634A>G has been reported in the literature as a compound heterozygous genotype in multiple well-genotyped individuals affected with PLA2G6-associated neurodegeneration with or without brain iron accumulation, including one case of de novo inheritance and multiple instances where it was in trans with a pathogenic variant (e.g. Guo_2017, de Souza_2017, Koh_2019, Kim_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same amino acid (p.Lys545Thr) has been observed in affected individuals in the HGMD database, suggesting Lys545 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 27395053, 31104286, 30302010, 28716262). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Infantile neuroaxonal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 545 of the PLA2G6 protein (p.Lys545Arg). This variant is present in population databases (rs121908681, gnomAD 0.03%). This missense change has been observed in individual(s) with PLA2G6-related conditions (PMID: 27395053, 30302010, 31104286). 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: 159741). 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 not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. This variant disrupts the p.Lys545 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 16783378, 19138334), which suggests that this may be a clinically significant amino acid residue. 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

- -

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.Lys545Arg variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 30302010, 27395053, 33835755, 28716262), and has been identified in 0.03% (6/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908681). 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. Of the 4 affected individuals, 2 were compound heterozygotes that carried reported likely pathogenic variants in trans, which increases the likelihood that the p.Lys545Arg variant is pathogenic (Variant ID: 279875; PMID: 30302010, 27395053). This variant was found to be de novo in 1 individual with confirmed paternity and maternity (PMID: 27395053). This variant has also been reported in ClinVar (Variation ID#: 159741) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Lys545Thr, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 16783378, 32581362; ClinVar ID: 6196). 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: PP3, PS2_moderate, PM3_strong, PM5 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

0.0038

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;.

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.83

MutPred

0.65

Gain of methylation at K545 (P = 0.0288);.;.;

MVP

0.87

MPC

0.67

ClinPred

0.86

GERP RS

5.5

Varity_R

0.79

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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