NM_003560.4:c.2222G>A

Variant names:

• chr22-38112558-C-T
• rs121908686
• NM_003560.4:c.2222G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM5 PP5_Very_Strong

The NM_003560.4(PLA2G6):​c.2222G>A​(p.Arg741Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,401,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004048240: Functional studies showed that this variant is unable to maintain mitochondrial function and is defective in preventing mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway (Chiu et al., 2017).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R741W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.83
• Publications: 41 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004048240: Functional studies showed that this variant is unable to maintain mitochondrial function and is defective in preventing mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway (Chiu et al., 2017).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003560.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-38112559-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 22-38112558-C-T is Pathogenic according to our data. Variant chr22-38112558-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	NM_003560.4	MANE Select	c.2222G>A	p.Arg741Gln	missense	Exon 16 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.2222G>A	p.Arg741Gln	missense	Exon 16 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.2060G>A	p.Arg687Gln	missense	Exon 15 of 16	NP_001004426.1	O60733-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.2222G>A	p.Arg741Gln	missense	Exon 16 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.2060G>A	p.Arg687Gln	missense	Exon 15 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.2264G>A	p.Arg755Gln	missense	Exon 16 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000903 AC: 14 AN: 154980 AF XY: 0.000145

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000337

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 59 AN: 1401016 Hom.: 0 Cov.: 31 AF XY: 0.0000520 AC XY: 36 AN XY: 691780

African (AFR) AF: 0.0000632 AC: 2 AN: 31650

American (AMR) AF: 0.00 AC: 0 AN: 36354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 35862

South Asian (SAS) AF: 0.000464 AC: 37 AN: 79716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.0000166 AC: 18 AN: 1081454

Other (OTH) AF: 0.0000344 AC: 2 AN: 58084

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000337 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000461 AC: 5

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Autosomal recessive Parkinson disease 14 (4)
3	-	-	Neurodegeneration with brain iron accumulation 2B (3)
3	-	-	not provided (3)
2	-	-	Infantile neuroaxonal dystrophy (2)
1	-	-	Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 (1)
1	-	-	Neurodegeneration with brain iron accumulation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.67
Sift	Benign	0.064	T
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.83
MVP		0.90
MPC		0.80
ClinPred		0.47	T
GERP RS		4.5
Varity_R		0.21
gMVP		0.34
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121908686; hg19: chr22-38508565;