Variant 22-38140038-GTTGCACCGAGCA-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4PP3PP5

The ENST00000332509.8(PLA2G6):c.729_740del(p.Ala244_Asn247del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PLA2G6
ENST00000332509.8 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 8.94

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a repeat ANK 3 (size 29) in uniprot entity PLPL9_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in ENST00000332509.8

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in ENST00000332509.8.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 22-38140038-GTTGCACCGAGCA-G is Pathogenic according to our data. Variant chr22-38140038-GTTGCACCGAGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159777.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.729_740del	p.Ala244_Asn247del	inframe_deletion	5/17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.729_740del	p.Ala244_Asn247del	inframe_deletion	5/17	1	NM_003560.4	ENSP00000333142	P3	O60733-1
	ENST00000624072.1 linkuse as main transcript	n.9830_9841del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248606

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134488

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1460790

Hom.:

AF XY:

0.00000963

AC XY:

AN XY:

726566

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 15, 2023

Variant summary: PLA2G6 c.729_740del12 (p.Ala244_Asn247del) results in an in-frame deletion that is predicted to remove 4 amino acids from the Ankyrin repeat (IPR002110) of the encoded protein. The variant allele was found at a frequency of 4e-06 in 248606 control chromosomes (gnomAD). c.729_740del12 has been reported in the literature in two siblings affected with PLA2G6-associated neurodegeneration (Al-Maawali_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Iron accumulation in brain

Pathogenic:1

Likely 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

Sep 18, 2023

In-frame deletion of 4 amino acids in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27516098) -

PLA2G6-associated neurodegeneration

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Jan 24, 2023

The p.Ala244_Asn247del variant in PLA2G6 has been reported in 1 individual, in the compound heterozygous state, with PLA2G6-associated neurodegeneration (PMID: 27516098), segregated with disease in 1 affected individual from 1 family (PMID: 27516098), and has been identified in 0.0009% (1/112430) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784360). 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#: 159777) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and as pathogenic by GeneDx. This variant is a deletion of 4 amino acids at position 244 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Ala244_Asn247del variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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