NM_003560.4:c.1442T>A

Variant names:

• chr22-38123244-A-T
• rs587784330
• NM_003560.4:c.1442T>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003560.4(PLA2G6):​c.1442T>A​(p.Leu481Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,462 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.87
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• neurodegeneration with brain iron accumulation 2B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• PLA2G6-associated neurodegeneration

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive Parkinson disease 14

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity PLPL9_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003560.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 22-38123244-A-T is Pathogenic according to our data. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38123244-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 159731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.1442T>A	p.Leu481Gln	missense_variant	Exon 11 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1442T>A	p.Leu481Gln	missense_variant	Exon 11 of 17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000592 AC: 1 AN: 168850 AF XY: 0.0000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407462 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694900

African (AFR) AF: 0.00 AC: 0 AN: 32108

American (AMR) AF: 0.0000544 AC: 2 AN: 36758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 36676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083398

Other (OTH) AF: 0.00 AC: 0 AN: 58340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile neuroaxonal dystrophy Pathogenic:2

Jun 02, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000159731 /PMID: 16783378 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16783378, 24870368). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 25164370). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 481 of the PLA2G6 protein (p.Leu481Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with PLA2G6-related conditions (PMID: 16783378, 24870368, 25164370). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 159731). 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

May 21, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodegeneration with brain iron accumulation 2B Pathogenic:1

Jan 16, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PLA2G6-associated neurodegeneration Pathogenic:1

Jan 24, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu481Gln variant in PLA2G6 has been reported in 8 individuals with PLA2G6-associated neurodegeneration (PMID: 18359254, Silva 2014, Pinto 2010, 16783378, Lissens 2008, 24870368, 25164370), and has been identified in 0.004% (1/25880) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784330). 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#: 159731) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago) and Institute of Human Genetics (Klinikum rechts der Isar). Of the 8 affected individuals, 2 of those were homozygotes, and 2 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.Leu481Gln variant is pathogenic. (Variant ID: 6195; PMID: 18359254, 25164370). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3_strong (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;.;.
PhyloP100		8.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		0.86		Loss of catalytic residue at L481 (P = 0.0227);.;.;
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587784330; hg19: chr22-38519251;