22-38145625-C-T

Position:

chr22-38145625-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003560.4(PLA2G6):c.238G>A(p.Ala80Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,066 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.42

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:

ENSG00000279080 (HGNC:):

ENSG00000279080 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 22-38145625-C-T is Pathogenic according to our data. Variant chr22-38145625-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38145625-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.238G>A	p.Ala80Thr	missense_variant	3/17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 link	c.238G>A	p.Ala80Thr	missense_variant	3/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249158

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460920

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726662

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3_VeryStrong+PP1_Strong+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 30, 2023	PM3_Strong, PS3_Moderate, PP1_Moderate, PM2 -

Infantile neuroaxonal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 80 of the PLA2G6 protein (p.Ala80Thr). This variant is present in population databases (rs121908685, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 16783378, 22934738, 30772976, 34622992). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6202). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PLA2G6 function (PMID: 26755131). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2022

Published functional studies demonstrate a damaging effect, as A80T fails to restore wild type protein function and results in significant deficits in neurological function in flies (Mori et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22934738, 30772976, 18799783, 19138334, 16783378, 26755131, 34622992, 35911906, 27196560, 31548400) -

PLA2G6-associated neurodegeneration

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 24, 2023

The p.Ala80Thr variant in PLA2G6 has been reported in 5 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 19138334, 27196560, 30772976, 34622992), segregated with disease in 2 individuals from 1 family (PMID: 30772976), and has been identified in 0.005% (1/18286) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908685). 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#: 6202) and has been interpreted as pathogenic by GeneDx and OMIM and as a variant of uncertain significance by Mayo Clinic Laboratories (Mayo Clinic) and Invitae. Of the 5 affected individuals, 1 of those was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Ala80Thr variant is pathogenic (VariationID: 30371; PMID: 27196560, 30772976). In vitro functional studies provide some evidence that the p.Ala80Thr variant may slightly impact protein function (PMID: 31548400). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM2_supporting, PP1, PM3_strong, PS3_supporting (Richards 2015). -

Neurodegeneration with brain iron accumulation 2B

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 28, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;D;.;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.6

M;M;M;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

D;N;N;D

REVEL

Uncertain

0.44

Sift

Benign

0.069

T;T;T;D

Sift4G

Benign

0.086

T;T;T;D

Polyphen

0.85

P;D;D;.

Vest4

0.73

MutPred

0.89

Loss of stability (P = 0.1277);Loss of stability (P = 0.1277);Loss of stability (P = 0.1277);Loss of stability (P = 0.1277);

MVP

0.87

MPC

0.87

ClinPred

0.94

GERP RS

5.3

Varity_R

0.25

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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