rs587784349

chr22-38112565-C-G

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.2215G>C(p.Asp739His) variant causes a missense change. The variant allele was found at a frequency of 0.0000367 in 1,552,372 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). Synonymous variant affecting the same amino acid position (i.e. D739D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 7.05

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_003560.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 22-38112565-C-G is Pathogenic according to our data. Variant chr22-38112565-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159761.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=3, Uncertain_significance=3}. Variant chr22-38112565-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.2215G>C	p.Asp739His	missense_variant	16/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.2215G>C	p.Asp739His	missense_variant	16/17	1	NM_003560.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000130 AC: 2 AN: 153362 Hom.: 0 AF XY: 0.0000244 AC XY: 2 AN XY: 81882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000343

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000386 AC: 54 AN: 1400246 Hom.: 0 Cov.: 31 AF XY: 0.0000448 AC XY: 31 AN XY: 691276

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: 0.0000481

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2016	The D739H variant in the PLA2G6 gene has been reported previously in patients with atypical NAD who were also heterozygous for a second variant in the gene (Morgan et al., 2006; Gregory et al., 2008). The D739H variant was not observed in approximately 6300 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 D739H variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G740R, R741W, R741Q) 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. We interpret D739H as a pathogenic variant. -

PLA2G6-associated neurodegeneration Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Asp739His variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 30120687, 18799783), segregated with disease in 1 affected relative from 1 family (PMID: 18799783), and has been identified in 0.006% (1/17170) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784349). 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#: 159761) and has been interpreted as a variant of uncertain significance by Illumina Laboratory Services and Invitae, and pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Asp739His variant is pathogenic (PMID: 30120687). 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.Asp739His variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM3_supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2017	The PLA2G6 c.2215G>C (p.Asp739His) variant has been reported in a compound heterozygous state with another missense variant in two related patients with atypical neuroaxonal dystrophy, which was initially categorized as idiopathic neurodegeneration with brain iron accumulation (Morgan et al. 2006; Gregory et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the Total population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Asp739His variant is therefore 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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 739 of the PLA2G6 protein (p.Asp739His). This variant is present in population databases (rs587784349, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 16783378; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159761). 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%. For these reasons, this variant has been classified as Pathogenic. -

Iron accumulation in brain Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2022

The c.2215G>C (p.D739H) alteration is located in exon 16 (coding exon 15) of the PLA2G6 gene. This alteration results from a G to C substitution at nucleotide position 2215, causing the aspartic acid (D) at amino acid position 739 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.81		Loss of loop (P = 0.0073);.;.;
MVP		0.95
MPC		0.90
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.67
gMVP		0.69

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: rs587784349; hg19: chr22-38508572;