rs374746113

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_003560.4(PLA2G6):c.386T>C(p.Leu129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 2.91

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-38145477-A-G is Pathogenic according to our data. Variant chr22-38145477-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159768.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3}. Variant chr22-38145477-A-G 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.386T>C	p.Leu129Pro	missense_variant	3/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.386T>C	p.Leu129Pro	missense_variant	3/17	1	NM_003560.4	P3	O60733-1
	ENST00000624072.1 linkuse as main transcript	n.15262A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000446

AC:

AN:

246764

Hom.:

AF XY:

0.0000450

AC XY:

AN XY:

133290

show subpopulations

Gnomad AFR exome

AF:

0.000696

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000110

AC:

AN:

1459730

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

725984

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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

AF:

0.000171

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000604

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Infantile neuroaxonal dystrophy

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 129 of the PLA2G6 protein (p.Leu129Pro). This variant is present in population databases (rs374746113, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 29395073, 34307755, 35247231). 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: 159768). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 14, 2019	The PLA2G6 c.386T>C (p.Leu129Pro) variant is a missense variant that has been reported in one study, in which it is found in one presumably compound heterozygous individual with a second missense variant (Gitiaux et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.000571 in the African/African-American population of the Genome Aggregation Database. Based on the limited evidence, the p.Leu129Pro variant is classified as a variant of uncertain significance for infantile neuroaxonal dystrophy 1. -
Likely pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Apr 01, 2022	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.386T>C (p.L129P) alteration is located in exon 3 (coding exon 2) of the PLA2G6 gene. This alteration results from a T to C substitution at nucleotide position 386, causing the leucine (L) at amino acid position 129 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (14/278142) total alleles studied. The highest observed frequency was 0.06% (14/24504) of African alleles. The p.L129P alteration has detected in the homozygous state and in trans with other PLA2G6 alterations in patients with features consistent with neurodegeneration with brain iron accumulation (Drecourt, 2018; Gitiaux, 2018; Ambry internal data). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2022

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: 26633542, 29395073, 29859652, 35247231, 34307755) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 23, 2021

Variant summary: PLA2G6 c.386T>C (p.Leu129Pro) results in a non-conservative amino acid change in 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 9.2e-05 in 391476 control chromosomes, predominantly at a frequency of 0.00066 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3.1). This frequency is somewhat lower than the maximum expected for a pathogenic variant in PLA2G6 causing Neurodegeneration with Brain Iron Accumulation (0.00085), allowing no conclusion about variant significance. The variant, c.386T>C, has been reported in the literature in at least one individual affected with Neurodegeneration with Brain Iron Accumulation, where a pathogenic (truncating) variant was reported in trans (Drecourt_2018, Gitiaux_2018). One of these publications also reported experimental evidence, demonstrating iron overload and TfR1 dysregulation in patient derived fibroblasts (Drecourt_2018). The variant was also reported in a patient with unspecified nervous system phenotype, where no variant in trans was specified (Retterer_2015), and in a recent case report of a patient affected with early-onset Parkinsonism with iron accumulation in the brain, who also carried a (potentially) pathogenic missense variant was in trans (Oliveira_2021). These data do not allow clear conclusions about variant significance. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Iron accumulation in brain

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

PLA2G6-associated neurodegeneration

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Jan 24, 2023

The p.Leu129Pro variant in PLA2G6 has been reported in 3 individuals with PLA2G6-associated neurodegeneration (PMID: 29859652, 34307755, 35247231) and has been identified in 0.06% (14/24504) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374746113). 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#: 159768) and has been interpreted as likely pathogenic by GeneDx and Ambry Genetics and as a variant of uncertain significance by Illumina Laboratory Services (Illumina), Invitae, Genetic Services Laboratory (University of Chicago), and Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Leu129Pro variant is pathogenic (PMID: 35247231). In vitro functional studies provide some evidence that the p.Leu129Pro variant may slightly impact protein function (PMID: 29395073). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu129Pro variant is uncertain. ACMG/AMP Criteria applied: PS3_moderate, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.010

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

M;M;M;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Benign

0.079

T;T;T;D

Polyphen

0.99

D;D;D;.

Vest4

0.65

MVP

0.78

MPC

0.97

ClinPred

0.52

GERP RS

5.3

Varity_R

0.62

gMVP

0.60

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