NM_003560.4:c.2246G>C

Variant names:

• chr22-38112534-C-G
• rs587784351
• NM_003560.4:c.2246G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_003560.4(PLA2G6):​c.2246G>C​(p.Trp749Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000128 in 1,402,780 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.03

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003560.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 22-38112534-C-G is Pathogenic according to our data. Variant chr22-38112534-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159763.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.2246G>C	p.Trp749Ser	missense_variant	Exon 16 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.2246G>C	p.Trp749Ser	missense_variant	Exon 16 of 17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000128 AC: 18 AN: 1402780 Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 7 AN XY: 692856

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: 0.0000157

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Apr 10, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W749S variant in the PLA2G6 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The W749S variant was not observed in approximately 6,350 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W749S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, numerous missense variants in nearby residues (R741Q; R741W; R745W; R745P; R747W; E751K; G754V) have been reported in the Human Gene Mutation Database in association with PLA2G6-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The W749S variant is a strong candidate for a disease-causing variant however, the possibility it may be a rare benign variant cannot be excluded -

Iron accumulation in brain Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 01, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PLA2G6 c.2246G>C (p.Trp749Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 157752 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2246G>C in individuals affected with Neurodegeneration With Brain Iron Accumulation and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 159763). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Infantile neuroaxonal dystrophy Uncertain:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 749 of the PLA2G6 protein (p.Trp749Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLA2G6-related conditions. ClinVar contains an entry for this variant (Variation ID: 159763). 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%. 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

Apr 30, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Trp749Ser variant in PLA2G6 has not been previously reported in the literature in individuals with PLA2G6-associated neurodegeneration, but has been identified in 0.001% (17/1150436) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784351). 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 (VCV000159763.14) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago) and GeneDx, and a variant of uncertain significance by Labcorp Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Trp749Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3_moderate (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-12	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.77		Loss of helix (P = 0.0072);.;.;
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587784351; hg19: chr22-38508541;