rs587784360
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP3PP5
The NM_003560.4(PLA2G6):c.729_740delTGCTCGGTGCAA(p.Ala244_Asn247del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,790 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: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
PLA2G6
NM_003560.4 disruptive_inframe_deletion
NM_003560.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.94
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_003560.4.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 22-38140038-GTTGCACCGAGCA-G is Pathogenic according to our data. Variant chr22-38140038-GTTGCACCGAGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159777.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248606Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134488
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1460790Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 726566
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurodegeneration with brain iron accumulation Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 15, 2023 | Variant summary: PLA2G6 c.729_740del12 (p.Ala244_Asn247del) results in an in-frame deletion that is predicted to remove 4 amino acids from the Ankyrin repeat (IPR002110) of the encoded protein. The variant allele was found at a frequency of 4e-06 in 248606 control chromosomes (gnomAD). c.729_740del12 has been reported in the literature in two siblings affected with PLA2G6-associated neurodegeneration (Al-Maawali_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Iron accumulation in brain Pathogenic:1
| Likely 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 | Sep 18, 2023 | In-frame deletion of 4 amino acids in a non-repeat region predicted to critically alter the protein; In silico analysis supports 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: 27516098) - |
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.Ala244_Asn247del variant in PLA2G6 has been reported in 1 individual, in the compound heterozygous state, with PLA2G6-associated neurodegeneration (PMID: 27516098), segregated with disease in 1 affected individual from 1 family (PMID: 27516098), and has been identified in 0.0009% (1/112430) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784360). 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#: 159777) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and as pathogenic by GeneDx. This variant is a deletion of 4 amino acids at position 244 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Ala244_Asn247del variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM4 (Richards 2015). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at