rs587784329
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003560.4(PLA2G6):c.1351delC(p.Leu451TyrfsTer20) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
PLA2G6
NM_003560.4 frameshift, splice_region
NM_003560.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.05
Publications
7 publications found
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 Gene-Disease associations (from GenCC):
- neurodegeneration with brain iron accumulation 2AInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
- neurodegeneration with brain iron accumulation 2BInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- PLA2G6-associated neurodegenerationInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- autosomal recessive Parkinson disease 14Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-38126446-AG-A is Pathogenic according to our data. Variant chr22-38126446-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 159730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_003560.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PLA2G6 | NM_003560.4 | MANE Select | c.1351delC | p.Leu451TyrfsTer20 | frameshift splice_region | Exon 10 of 17 | NP_003551.2 | ||
| PLA2G6 | NM_001349864.2 | c.1351delC | p.Leu451TyrfsTer20 | frameshift splice_region | Exon 10 of 17 | NP_001336793.1 | |||
| PLA2G6 | NM_001004426.3 | c.1189delC | p.Leu397TyrfsTer20 | frameshift splice_region | Exon 9 of 16 | NP_001004426.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PLA2G6 | ENST00000332509.8 | TSL:1 MANE Select | c.1351delC | p.Leu451TyrfsTer20 | frameshift splice_region | Exon 10 of 17 | ENSP00000333142.3 | ||
| PLA2G6 | ENST00000402064.5 | TSL:1 | c.1189delC | p.Leu397TyrfsTer20 | frameshift splice_region | Exon 9 of 16 | ENSP00000386100.1 | ||
| PLA2G6 | ENST00000664587.1 | c.1213delC | p.Leu405TyrfsTer20 | frameshift | Exon 9 of 16 | ENSP00000499394.1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
3
AN:
152076
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad FIN
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.00000401 AC: 1AN: 249206 AF XY: 0.00000741 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
249206
AF XY:
Gnomad AFR exome
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Gnomad NFE exome
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460516Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726612 show subpopulations
GnomAD4 exome
AF:
AC:
11
AN:
1460516
Hom.:
Cov.:
30
AF XY:
AC XY:
4
AN XY:
726612
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33466
American (AMR)
AF:
AC:
5
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
AC:
0
AN:
52664
Middle Eastern (MID)
AF:
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
AC:
6
AN:
1111488
Other (OTH)
AF:
AC:
0
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.443
Heterozygous variant carriers
0
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Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74296 show subpopulations
GnomAD4 genome
AF:
AC:
3
AN:
152076
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74296
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41388
American (AMR)
AF:
AC:
3
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5182
South Asian (SAS)
AF:
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68012
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Infantile neuroaxonal dystrophy (2)
1
-
-
Iron accumulation in brain (1)
1
-
-
not provided (1)
1
-
-
PLA2G6-associated neurodegeneration (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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