rs121908687
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_003560.4(PLA2G6):c.2239C>T(p.Arg747Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,402,052 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. R747Q) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
PLA2G6
NM_003560.4 missense
NM_003560.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 2.01
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003560.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 22-38112541-G-A is Pathogenic according to our data. Variant chr22-38112541-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38112541-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PLA2G6 | NM_003560.4 | c.2239C>T | p.Arg747Trp | missense_variant | 16/17 | ENST00000332509.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PLA2G6 | ENST00000332509.8 | c.2239C>T | p.Arg747Trp | missense_variant | 16/17 | 1 | NM_003560.4 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000258 AC: 4AN: 155016Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 83066
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GnomAD4 exome AF: 0.0000178 AC: 25AN: 1402052Hom.: 0 Cov.: 31 AF XY: 0.0000173 AC XY: 12AN XY: 692434
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive Parkinson disease 14 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 11, 2014 | This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 24-year-old male with adult-onset progressive lower limb weakness/stiffness, spastic gait, hyperthyroidism, diffuse brain atrophy, simialrly affected brother (not tested). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 04, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Homozygote Missense variant c.2239C>T in Exon 16 of the PLA2G6 gene that results in the amino acid substitution p.Arg747Trp was identified. The observed variant has a minor allele frequency of 0.0003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic/Likely pathogenicwith a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 6204 as of 2022-12-24). Mutations in the gene have been associated with alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids (Paisan-Ruiz C et al., 2009; Engel LA et al., 2010). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2009 | - - |
Infantile neuroaxonal dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 747 of the PLA2G6 protein (p.Arg747Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with PLA2G6-related conditions (PMID: 18570303, 27127721, 28295203). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6204). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PLA2G6 function (PMID: 20886109, 26755131). This variant disrupts the p.Arg747 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 35861376; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
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.Arg747Trp variant in PLA2G6 has been reported at least 6 individuals with PLA2G6-associated neurodegeneration (PMID: 18570303, 27127721, 30868093, 28295203, 35152491, Park_2019), segregated with disease in 2 affected relatives from 2 families (PMID: 28295203, Park_2019), and has been identified in 0.01% (3/23206) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs751225193). 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 6 affected individuals, all were homozygotes, which increases the likelihood that the p.Arg747Trp variant is pathogenic (PMID: 18570303, 27127721, 30868093, 28295203, 35152491, Park_2019). This variant has also been reported in ClinVar (Variation ID#: 6204) and has been interpreted as pathogenic or likely pathogenic by Fulgent Genetics, Baylor Genetics, Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen), and OMIM. In vitro functional studies provide some evidence that the p.Arg747Trp variant may impact protein function (PMID: 26001724, 26755131, 20886109). 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: 26755131). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous for this variant is highly specific for PLA2G6-associated neurodegeneration based on brain iron accumulation on MRI consistent with disease (PMID: 30868093, 28295203). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3, PP3, PS3, PP1, PP4 (Richards 2015). - |
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 | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of helix (P = 0.0117);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at