rs11570680

Positions:

chr22-38132881-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003560.4(PLA2G6):c.1027G>A(p.Ala343Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,553,716 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 6 hom., cov: 33)

Exomes 𝑓: 0.012 ( 136 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.26

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031460226).

BP6

Variant 22-38132881-C-T is Benign according to our data. Variant chr22-38132881-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38132881-C-T is described in Lovd as [Benign]. Variant chr22-38132881-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00918 (1399/152360) while in subpopulation SAS AF= 0.0153 (74/4828). AF 95% confidence interval is 0.0125. There are 6 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1027G>A	p.Ala343Thr	missense_variant	7/17	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.1027G>A	p.Ala343Thr	missense_variant	7/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.00920

AC:

1401

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00715

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0110

AC:

1757

AN:

159972

Hom.:

AF XY:

0.0121

AC XY:

1027

AN XY:

85004

show subpopulations

Gnomad AFR exome

AF:

0.00254

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000169

Gnomad SAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.00808

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0121

AC:

16997

AN:

1401356

Hom.:

136

Cov.:

AF XY:

0.0125

AC XY:

8670

AN XY:

691800

show subpopulations

Gnomad4 AFR exome

AF:

0.00205

Gnomad4 AMR exome

AF:

0.00645

Gnomad4 ASJ exome

AF:

0.0174

Gnomad4 EAS exome

AF:

0.000139

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.00716

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.0117

GnomAD4 genome

AF:

0.00918

AC:

1399

AN:

152360

Hom.:

Cov.:

AF XY:

0.00938

AC XY:

699

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00888

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.00715

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.00952

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00208

AC:

ESP6500EA

AF:

0.0128

AC:

109

ExAC

AF:

0.00664

AC:

750

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2019	This variant is associated with the following publications: (PMID: 25174650, 27393345, 30340910) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PLA2G6: BP4, BS1, BS2 -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Infantile neuroaxonal dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

PLA2G6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

PLA2G6-associated neurodegeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

D;D;.

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.37

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.032

B;B;B

Vest4

0.12

MPC

0.26

ClinPred

0.017

GERP RS

3.1

Varity_R

0.052

gMVP

0.76

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