22-38145647-G-T

Variant names:

• chr22-38145647-G-T
• rs774631197
• NM_003560.4:c.216C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_003560.4(PLA2G6):​c.216C>A​(p.Phe72Leu) variant causes a missense change. 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F72F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.67
• Publications: 10 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

ENSG00000279080 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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, 0.792
• PP5: Variant 22-38145647-G-T is Pathogenic according to our data. Variant chr22-38145647-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30368.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	NM_003560.4	MANE Select	c.216C>A	p.Phe72Leu	missense	Exon 3 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.216C>A	p.Phe72Leu	missense	Exon 3 of 17	NP_001336793.1
	PLA2G6	NM_001004426.3		c.216C>A	p.Phe72Leu	missense	Exon 3 of 16	NP_001004426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.216C>A	p.Phe72Leu	missense	Exon 3 of 17	ENSP00000333142.3
	PLA2G6	ENST00000402064.5	TSL:1	c.216C>A	p.Phe72Leu	missense	Exon 3 of 16	ENSP00000386100.1
	PLA2G6	ENST00000668949.1		c.216C>A	p.Phe72Leu	missense	Exon 3 of 17	ENSP00000499711.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive Parkinson disease 14 Pathogenic:1

Oct 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.44		Loss of loop (P = 0.0374)
MVP		0.91
MPC		0.87
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.47
gMVP		0.61
Mutation Taster		=1/99	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: rs774631197; hg19: chr22-38541654;