Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_003560.4(PLA2G6):c.3G>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PLA2G6
NM_003560.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.96

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 179 codons. Genomic position: 38143179. Lost 0.221 part of the original CDS.

PS1

Another start lost variant in NM_003560.4 (PLA2G6) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-38169424-C-A is Pathogenic according to our data. Variant chr22-38169424-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 429031.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	NM_003560.4	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 2 of 17	NP_003551.2
PLA2G6	NM_001349864.2		c.3G>T	p.Met1?	start_lost	Exon 2 of 17	NP_001336793.1
PLA2G6	NM_001004426.3		c.3G>T	p.Met1?	start_lost	Exon 2 of 16	NP_001004426.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 2 of 17	ENSP00000333142.3
PLA2G6	ENST00000402064.5	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 2 of 16	ENSP00000386100.1
PLA2G6	ENST00000668949.1		c.3G>T	p.Met1?	start_lost	Exon 2 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727116

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111856

Other (OTH)

AF:

0.00

AC:

AN:

60390

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Infantile neuroaxonal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.39

PhyloP100

5.0

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.98

Gain of catalytic residue at M1 (P = 0.0387)

MVP

0.89

ClinPred

0.99

GERP RS

4.6

Varity_R

0.81

gMVP

0.78

Mutation Taster

=1/199

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.

rs764959600

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over