rs587784353

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_2371del(p.Tyr790Ter) variant causes a stop gained, 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 stop_gained, frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.13

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:

Genome browser will be placed here

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 6 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	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.2370_2371del	p.Tyr790Ter	stop_gained, frameshift_variant	17/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.2370_2371del	p.Tyr790Ter	stop_gained, frameshift_variant	17/17	1	NM_003560.4	P3	O60733-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000330

AC:

AN:

242472

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131346

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000549

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000707

AC:

103

AN:

1457762

Hom.:

AF XY:

0.0000828

AC XY:

AN XY:

724814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000910

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000529

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	Invitae	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) -

Neurodegeneration with brain iron accumulation 2B

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 28, 2008

- -

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‚Äôs 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). -

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

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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