rs11570680

chr22-38132881-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A343E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0092 (6 hom., cov: 33)
  • Exomes 𝑓: 0.012 (136 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.26

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003560.4
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.1027G>A	p.Ala343Thr	missense_variant	7/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1027G>A	p.Ala343Thr	missense_variant	7/17	1	NM_003560.4	P3
	ENST00000624072.1	n.2666C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1401 AN: 152242 Hom.: 6 Cov.: 33

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.: 21 AF XY: 0.0121 AC XY: 1027 AN XY: 85004

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.: 31 AF XY: 0.0125 AC XY: 8670 AN XY: 691800

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.: 6 Cov.: 33 AF XY: 0.00938 AC XY: 699 AN XY: 74514

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.: 25

Bravo AF: 0.00952

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00208 AC: 9

ESP6500EA AF: 0.0128 AC: 109

ExAC AF: 0.00664 AC: 750

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ENSG00000279080: BS1, BS2; PLA2G6: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2019	This variant is associated with the following publications: (PMID: 25174650, 27393345, 30340910) -

PLA2G6-related condition Benign:1

Likely benign, criteria provided, single submitter

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). -

Infantile neuroaxonal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;D;.
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.37	N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs11570680; hg19: chr22-38528888;