rs587784353
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003560.4(PLA2G6):c.2370_2371delTG(p.Tyr790fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000665 in 1,609,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000071 ( 0 hom. )
Consequence
PLA2G6
NM_003560.4 frameshift
NM_003560.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.13
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 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-38112210-TCA-T is Pathogenic according to our data. Variant chr22-38112210-TCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38112210-TCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLA2G6 | NM_003560.4 | c.2370_2371delTG | p.Tyr790fs | frameshift_variant | 17/17 | ENST00000332509.8 | NP_003551.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLA2G6 | ENST00000332509.8 | c.2370_2371delTG | p.Tyr790fs | frameshift_variant | 17/17 | 1 | NM_003560.4 | ENSP00000333142.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000330 AC: 8AN: 242472Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131346
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GnomAD4 exome AF: 0.0000707 AC: 103AN: 1457762Hom.: 0 AF XY: 0.0000828 AC XY: 60AN XY: 724814
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Infantile neuroaxonal dystrophy Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Tyr790*) in the PLA2G6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PLA2G6 protein. This variant is present in population databases (rs587784353, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 16783378, 27378808, 29915382; Invitae). ClinVar contains an entry for this variant (Variation ID: 6201). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PLA2G6 function (PMID: 20886109). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jan 28, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 28, 2008 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2021 | The c.2370_2371delTG (p.Y790*) alteration, located in exon 17 (coding exon 16) of the PLA2G6 gene, consists of a deletion of 2 nucleotides from position 2370 to 2371. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 790. This alteration occurs at the 3' terminus of the PLA2G6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 17/806 (2%) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function. Based on data from the Genome Aggregation Database (gnomAD) database, the PLA2G6 c.2370_2371delTG alteration was observed in 0.0033% (8/242472) of total alleles studied. The p.Y790* alteration has been reported in the homozygous and compound heterozygous state in multiple patients with PLA2G6-associated neurodegenerative disorders (Morgan, 2006; Gregory, 2008; Paisán-Ruiz, 2012; Sun, 2019). Functional studies demonstrate that the p.Y790* alteration has less than 10% catalytic activity in two substrates compared to wild type (Engel, 2010). Based on the available evidence, this alteration is classified as pathogenic. - |
Iron accumulation in brain Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16783378, 18799783, 29915382) - |
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 c.2370_2371delTG variant in PLA2G6 has been reported in at least 5 individuals with PLA2G6-associated neurodegeneration (PMID: 18799783, 20619503, 29915382, 16783378), and has been identified in 0.007% (1/15202) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784353). 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#: 6201) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago), GeneDx, Baylor Genetics, Invitae, Centogene AG - the Rare Disease Company, and OMIM. Of the 5 affected individuals, 1 of those was a homozygote, and 3 were compound heterozygotes that carried reported likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the c.2370_2371delTG variant is pathogenic (PMID: 18799783, 20619503, 29915382; ClinVar ID: 929943). In vitro functional studies provide some evidence that the p.Tyr790Ter variant may slightly impact protein function (PMID: 20886109). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 790 and leads to a premature termination codon at the same position. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. 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: PVS1_moderate, PM2_supporting, PM3_strong, PS3_supporting (Richards 2015). - |
Neurodegeneration with brain iron accumulation 2B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 28, 2008 | - - |
Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 13, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
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