rs794729212

Variant names:

• chr22-38115619-C-T
• rs794729212
• NM_003560.4:c.1942G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_003560.4(PLA2G6):​c.1942G>A​(p.Gly648Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.47
• Publications: 2 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 14 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-38115619-C-T is Pathogenic according to our data. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38115619-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 242578.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.1942G>A	p.Gly648Arg	missense_variant	Exon 14 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1942G>A	p.Gly648Arg	missense_variant	Exon 14 of 17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000108 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile neuroaxonal dystrophy Pathogenic:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 21, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.61		Gain of MoRF binding (P = 0.0305);.;.;
MVP		0.96
MPC		0.95
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.83
Mutation Taster		=33/67	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794729212; hg19: chr22-38511626; COSMIC: COSV59268450; COSMIC: COSV59268450;