NM_003560.4:c.238G>A

Variant names:

• chr22-38145625-C-T
• rs121908685
• NM_003560.4:c.238G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003560.4(PLA2G6):​c.238G>A​(p.Ala80Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,066 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 (★★). ClinVar reports functional evidence for this variant: "SCV001758287: Published functional studies demonstrate a damaging effect, as A80T fails to restore wild type protein function and results in significant deficits in neurological function in flies (Mori et al., 2019)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A80S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.42
• Publications: 18 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)

ENSG00000279080 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001758287: Published functional studies demonstrate a damaging effect, as A80T fails to restore wild type protein function and results in significant deficits in neurological function in flies (Mori et al., 2019).; SCV003761028: In vitro functional studies provide some evidence that the p.Ala80Thr variant may slightly impact protein function (PMID: 31548400).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-38145625-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1474450.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 22-38145625-C-T is Pathogenic according to our data. Variant chr22-38145625-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6202.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.238G>A	p.Ala80Thr	missense	Exon 3 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.238G>A	p.Ala80Thr	missense	Exon 3 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.238G>A	p.Ala80Thr	missense	Exon 3 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.238G>A	p.Ala80Thr	missense	Exon 3 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.238G>A	p.Ala80Thr	missense	Exon 3 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.238G>A	p.Ala80Thr	missense	Exon 3 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152028 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249158 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460920 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726662

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111598

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41508

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 (3)
1	-	-	Infantile neuroaxonal dystrophy (1)
1	-	-	Neurodegeneration with brain iron accumulation 2B (1)
1	-	-	not provided (1)
1	-	-	PLA2G6-associated neurodegeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.44
Sift	Benign	0.069	T
Sift4G	Benign	0.086	T
Polyphen		0.85	P
Vest4		0.73
MutPred		0.89		Loss of stability (P = 0.1277)
MVP		0.87
MPC		0.87
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.74
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121908685; hg19: chr22-38541632;