rs587784339

Positions:

chr22-38115658-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003560.4(PLA2G6):c.1903C>T(p.Arg635*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,544,374 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-38115658-G-A is Pathogenic according to our data. Variant chr22-38115658-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 159749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115658-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.1903C>T	p.Arg635*	stop_gained	14/17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 link	c.1903C>T	p.Arg635*	stop_gained	14/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

146324

Hom.:

AF XY:

0.0000633

AC XY:

AN XY:

78984

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000798

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000844

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000512

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.0000323

AC:

AN:

1392264

Hom.:

Cov.:

AF XY:

0.0000364

AC XY:

AN XY:

687058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000625

Gnomad4 AMR exome

AF:

0.0000549

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000352

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000662

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000876

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile neuroaxonal dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 16783378). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another variant in affected individuals: a 4-year-old female with regression,hypotonia, strabismus; a 5-year-old female with regression, hearing loss, vision loss, hypotonia, joint contactures. Heterozygotes would be expected to be asymptomatic carriers. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Arg635*) in the PLA2G6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLA2G6 are known to be pathogenic (PMID: 16783378, 18570303, 18799783, 22213678). This variant is present in population databases (rs587784339, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (PMID: 16783378, 22934738, 24108619, 25164370). ClinVar contains an entry for this variant (Variation ID: 159749). For these reasons, this variant has been classified as Pathogenic. -

PLA2G6-associated neurodegeneration

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2016	The p.Arg635X variant in PLA2G6 has been reported in 4 individuals with PLA2G6-a ssociated neurodegeneration, including one homozygote and 3 compound heterozygot es (Morgan 2006, Romani 2014, Sawyer 2014). Data from large population studies is insufficient to assess the frequency of this variant. This nonsense variant l eads to a premature termination codon at position 635 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria t o be classified as pathogenic for PLA2G6-associated neurodegeneration in an auto somal recessive manner. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Arg635Ter variant in PLA2G6 has been reported in at least 7 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 18799783, 22934738, 29859652, 25164370), segregated with disease in 1 affected relative from 1 family (PMID: 25164370), and has been identified in 0.008% (1/11852) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784339). 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#: 159749) and has been interpreted as pathogenic by multiple labs. Of the 7 affected individuals, 3 of those were homozygotes, which increases the likelihood that the p.Arg635Ter variant is pathogenic (PMID: 16783378, 18799783, 22934738 29859652). This nonsense variant leads to a premature termination codon at position 635, which is predicted to lead to a truncated or absent protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 07, 2020	The PLA2G6 c.1903C>T (p.Arg635Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg635Ter variant has been reported in at least five studies, in which it is found in a total of seven unrelated individuals, including in three in a homozygous state and in four in a compound heterozygous state (Morgan et al. 2006; Zhang et al. 2013; Sawyer et al. 2014; Romani et al. 2015; Darling et al. 2019). The clinical presentation of affected individuals was infant-onset of psychomotor regression or delay, hypotonia, strabismus, nystagmus, cerebellar atrophy, and variable brain iron accumulation. Control data are unavailable for this variant, which is reported at a frequency of 0.000051 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the p.Arg635Ter variant is classified as pathogenic for PLA2G6-associated neurodegeneration. -

Iron accumulation in brain

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2022

Observed with a second variant in affected individuals in published literature, but it is not known whether the variants occurred on the same (in cis) or opposite (in trans) chromosomes (Morgan et al., 2006; Sawyer et al., 2014; Romani et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Also denoted as R581X due to alternative nomenclature; This variant is associated with the following publications: (PMID: 25525159, 29859652, 32357911, 22934738, 25744623, 28091863, 29482223, 30340910, 25164370, 31689548, 31589614, 27535533, 24108619, 16783378) -

Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

Vest4

0.96

GERP RS

4.5

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

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