NM_003560.4:c.2098C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_003560.4(PLA2G6):c.2098C>T(p.Gln700*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,350 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 7.61

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

neurodegeneration with brain iron accumulation 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
neurodegeneration with brain iron accumulation 2B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
PLA2G6-associated neurodegeneration
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive Parkinson disease 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

PLA2G6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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 22-38113591-G-A is Pathogenic according to our data. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758. Variant chr22-38113591-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159758.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.2098C>T	p.Gln700*	stop_gained	Exon 15 of 17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 link	c.2098C>T	p.Gln700*	stop_gained	Exon 15 of 17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251440

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461350

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111678

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLA2G6: PM2, PVS1:Moderate, PP4 -

Jul 09, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile neuroaxonal dystrophy

Pathogenic:1

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln700*) in the PLA2G6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLA2G6 are known to be pathogenic (PMID: 16783378, 18570303, 18799783, 22213678). This variant is present in population databases (rs587784346, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with PLA2G6-related conditions (PMID: 27848944). ClinVar contains an entry for this variant (Variation ID: 159758). For these reasons, this variant has been classified as Pathogenic. -

Iron accumulation in brain

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLA2G6-associated neurodegeneration

Pathogenic:1

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Gln700Ter variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 27848944, 23100014) and has been identified in 0.0009% (1/113726) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784346). 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#: 159758) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago) and PerkinElmer Genomics. Of the 2 affected individuals, both of them were homozygotes, which increases the likelihood that the p.Gln700Ter variant is pathogenic (PMID: 27848944, 23100014). This nonsense variant leads to a premature termination codon at position 700, which is predicted to lead to a truncated or absent protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). -

Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14

Pathogenic:1

Jan 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.6

Vest4

0.97

GERP RS

4.4

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over