rs121908687

Variant names:

• chr22-38112541-G-A
• rs121908687
• NM_003560.4:c.2239C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-38112541-G-A
• chr22-38112541-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003560.4(PLA2G6):​c.2239C>T​(p.Arg747Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,402,052 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R747Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.01
• Publications: 45 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.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003560.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 22-38112541-G-A is Pathogenic according to our data. Variant chr22-38112541-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6204.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.2239C>T	p.Arg747Trp	missense	Exon 16 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.2239C>T	p.Arg747Trp	missense	Exon 16 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.2077C>T	p.Arg693Trp	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.2239C>T	p.Arg747Trp	missense	Exon 16 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.2077C>T	p.Arg693Trp	missense	Exon 15 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.2281C>T	p.Arg761Trp	missense	Exon 16 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000258 AC: 4 AN: 155016 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1402052 Hom.: 0 Cov.: 31 AF XY: 0.0000173 AC XY: 12 AN XY: 692434

African (AFR) AF: 0.0000316 AC: 1 AN: 31668

American (AMR) AF: 0.00 AC: 0 AN: 36496

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25262

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35894

South Asian (SAS) AF: 0.000125 AC: 10 AN: 79846

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 47002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000832 AC: 9 AN: 1082080

Other (OTH) AF: 0.0000344 AC: 2 AN: 58146

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000102 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000910 AC: 1

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.94		Gain of helix (P = 0.0117)
MVP		0.94
MPC		0.90
ClinPred		0.90	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.73
Mutation Taster		=72/28	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: rs121908687; hg19: chr22-38508548;