Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003560.4(PLA2G6):c.898G>A(p.Ala300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,561,942 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 7 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.12

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:

ENSG00000279080 (HGNC:):

ENSG00000279080 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0079809725).

BP6

Variant 22-38133010-C-T is Benign according to our data. Variant chr22-38133010-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235257.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000288 (406/1409566) while in subpopulation SAS AF = 0.00457 (366/80134). AF 95% confidence interval is 0.00418. There are 7 homozygotes in GnomAdExome4. There are 302 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	NM_003560.4	MANE Select	c.898G>A	p.Ala300Thr	missense	Exon 7 of 17	NP_003551.2
PLA2G6	NM_001349864.2		c.898G>A	p.Ala300Thr	missense	Exon 7 of 17	NP_001336793.1
PLA2G6	NM_001004426.3		c.898G>A	p.Ala300Thr	missense	Exon 7 of 16	NP_001004426.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.898G>A	p.Ala300Thr	missense	Exon 7 of 17	ENSP00000333142.3
PLA2G6	ENST00000402064.5	TSL:1	c.898G>A	p.Ala300Thr	missense	Exon 7 of 16	ENSP00000386100.1
PLA2G6	ENST00000668949.1		c.898G>A	p.Ala300Thr	missense	Exon 7 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000726

AC:

124

AN:

170682

AF XY:

0.00107

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:

0.0000567

Gnomad OTH exome

AF:

0.000428

GnomAD4 exome

AF:

0.000288

AC:

406

AN:

1409566

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

302

AN XY:

696688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32386

American (AMR)

AF:

0.00

AC:

AN:

37376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25272

East Asian (EAS)

AF:

0.00

AC:

AN:

36936

South Asian (SAS)

AF:

0.00457

AC:

366

AN:

80134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46678

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.0000276

AC:

AN:

1086594

Other (OTH)

AF:

0.000154

AC:

AN:

58536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000164

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000539

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Infantile neuroaxonal dystrophy (1)

Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 (1)

PLA2G6-associated neurodegeneration (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.75

M_CAP

Benign

0.013

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.76

PhyloP100

2.1

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.60

REVEL

Benign

0.090

Sift

Benign

0.32

Sift4G

Benign

0.33

Polyphen

0.026

Vest4

0.11

MVP

0.78

MPC

0.25

ClinPred

0.037

GERP RS

5.6

Varity_R

0.047

gMVP

0.59

Mutation Taster

=100/0

polymorphism

(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.

rs528966598

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over