NM_003560.4:c.1489C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_003560.4(PLA2G6):c.1489C>T(p.Leu497Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,401,732 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).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.33

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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003560.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

PP5

Variant 22-38123197-G-A is Pathogenic according to our data. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732. Variant chr22-38123197-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159732.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.1489C>T	p.Leu497Phe	missense_variant	Exon 11 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.1489C>T	p.Leu497Phe	missense_variant	Exon 11 of 17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000621

AC:

AN:

160936

AF XY:

0.0000118

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:

0.0000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1401732

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31794

American (AMR)

AF:

0.00

AC:

AN:

36044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

36104

South Asian (SAS)

AF:

0.00

AC:

AN:

79316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5206

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1080556

Other (OTH)

AF:

0.0000344

AC:

AN:

58098

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000536

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Iron accumulation in brain

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLA2G6-associated neurodegeneration

Uncertain:1

Jan 24, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Leu497Phe variant in PLA2G6 has not been previously reported in the literature in individuals with PLA2G6-associated neurodegeneration, but has been identified in 0.002% (1/63308) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784331). 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#: 159732) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu497Phe variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;.

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.8

H;.;.

PhyloP100

4.3

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.64

MutPred

0.70

Gain of helix (P = 0.0117);.;.;

MVP

0.92

MPC

0.86

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.91

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over