22-38143275-C-T

Position:

chr22-38143275-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003560.4(PLA2G6):c.439G>A(p.Ala147Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,612,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.902

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:

PLA2G6 (HGNC:):

PLA2G6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03951013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.439G>A	p.Ala147Thr	missense_variant	4/17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.439G>A	p.Ala147Thr	missense_variant	4/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

249792

Hom.:

AF XY:

0.0000814

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

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:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000952

AC:

139

AN:

1460128

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

726452

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000358

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:

0.0000998

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000197

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2022	Previously reported in an individual with infantile neuroaxonal dystrophy who also harbored a second variant in the PLA2G6 gene, however parental studies and segregation information were not provided (Morgan et al., 2006); However, the same genotype reported in this Morgan 2006 has subsequently been reported in the same chromosome (in cis) of two asymptomatic individuals who had a reported family history of infantile neuroaxonal dystrophy (Allouche et al., 2020).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16783378, 31894249, 27467583, 35803092, 26740555, 18799783, 27149842, 28719003, 33361639) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 19, 2021

Variant summary: PLA2G6 c.439G>A (p.Ala147Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 249792 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLA2G6 causing Neurodegeneration With Brain Iron Accumulation (0.00013 vs 0.00085), allowing no conclusion about variant significance. c.439G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with features of Neurodegeneration With Brain Iron Accumulation such as infantile neuroaxonal dystrophy (INAD) and has been subsequently cited by others (example, Morgan_2006, Kapoor_2016). However, the same compound heterozygous genotype reported in this individual has subsequently been reported in the same chromosome (in cis) of two asymptomatic individuals who had a reported family history of infantile neuroaxonal dystrophy (example, Allouche_2020). The authors concluded that these variants are not responsible for the associated phenotype of autosomal recessive infantile neuroaxonal dystrophy. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Neurodegeneration With Brain Iron Accumulation and/or INAD. 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 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Infantile neuroaxonal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 147 of the PLA2G6 protein (p.Ala147Thr). This variant is present in population databases (rs138672490, gnomAD 0.03%). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 16783378). ClinVar contains an entry for this variant (Variation ID: 341647). 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 not expected to disrupt PLA2G6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

PLA2G6-associated neurodegeneration

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 30, 2018

The PLA2G6 c.439G>A (p.Ala147Thr) missense variant has been reported in a compound heterozygous state in one individual with classic infantile neuroaxonal dystrophy (Morgan et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.001135 in the African American population from the Exome Sequencing Project. The evidence for this variant is limited. Therefore, the p.Ala147Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.077

T;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.14

T;T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.42

N;N;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

0.16

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.81

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.63

MVP

0.58

MPC

0.23

ClinPred

0.0073

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.015

gMVP

0.13

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

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