22-38115657-C-T

Position:

chr22-38115657-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_003560.4(PLA2G6):c.1904G>A(p.Arg635Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,382,584 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 7.39

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_pathogenic. Variant got 7 ACMG points.

PM1

In a domain PNPLA (size 184) in uniprot entity PLPL9_HUMAN there are 36 pathogenic changes around while only 3 benign (92%) in NM_003560.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

PP5

Variant 22-38115657-C-T is Pathogenic according to our data. Variant chr22-38115657-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30366.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1904G>A	p.Arg635Gln	missense_variant	14/17	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.1904G>A	p.Arg635Gln	missense_variant	14/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000147

AC:

AN:

135906

Hom.:

AF XY:

0.0000276

AC XY:

AN XY:

72440

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000855

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1382584

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

681010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000632

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000930

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000351

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PLA2G6-associated neurodegeneration

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Arg635Gln variant in PLA2G6 has been reported in 8 individuals with PLA2G6-associated neurodegeneration (PMID: 20938027, 30302010, 32771225), segregated with disease in 1 affected relative from 1 family (PMID: 20938027), and has been identified in 0.009% (1/11702) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs387906863). 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#: 30366) and has been interpreted as a variant of uncertain significance by Illumina Laboratory Services (Illumina) and as pathogenic by OMIM. Of the 8 affected individuals, 1 of those was a homozygote, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Gly653Ser variant is pathogenic (PMID: 20938027, 30302010, 32771225). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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, PM2_supporting, PM3_strong (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 26, 2018	The PLA2G6 c.1904G>A (p.Arg635Gln) missense variant has been reported in a compound heterozygous state in three Japanese individuals with early-onset (<30 years) parkinsonism with dementia and frontotemporal lobar atrophy (Yoshino et al. 2010). Two of these individuals were brothers, and all three shared a common haplotype. This variant was also reported in a homozygous state in a Japanese individual with adult-onset (age 66 years) spastic paraplegia with parkinsonism (Koh et al. 2018). This individual had an older sibling with a similar phenotype, but the sibling did not undergo genetic testing. The p.Arg635Gln variant was identified in one out of 2722 Japanese control chromosomes and is reported at a frequency of 0.000738 in the East Asian population of the Exome Aggregation Consortium. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Arg635Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Infantile neuroaxonal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 635 of the PLA2G6 protein (p.Arg635Gln). This variant is present in population databases (rs387906863, gnomAD 0.009%). This missense change has been observed in individuals with early onset Parkinson disease (PMID: 20938027, 32771225). ClinVar contains an entry for this variant (Variation ID: 30366). 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 with a positive predictive value of 80%. 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

Oct 12, 2010

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32183746, 26196026, 25601130, 30302010, 20938027, 32771225) -

Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.3

M;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.025

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.96

MutPred

0.67

Loss of MoRF binding (P = 0.0135);.;.;

MVP

0.96

MPC

0.63

ClinPred

0.98

GERP RS

4.5

Varity_R

0.58

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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