chr22-38127239-C-G

Variant names:

• chr22-38127239-C-G
• rs3788533
• NM_003560.4:c.1349-790G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003560.4(PLA2G6):​c.1349-790G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,217,292 control chromosomes in the GnomAD database, including 168,259 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17387 hom., cov: 33)
  • Exomes 𝑓: 0.53 (150872 hom.)
• Consequence: PLA2G6 NM_003560.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.75
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

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.1349-790G>C		intron	N/A	NP_003551.2
	PLA2G6	NM_001349864.2		c.1349-790G>C		intron	N/A	NP_001336793.1
	PLA2G6	NM_001004426.3		c.1187-790G>C		intron	N/A	NP_001004426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.1349-790G>C		intron	N/A	ENSP00000333142.3
	PLA2G6	ENST00000402064.5	TSL:1	c.1187-790G>C		intron	N/A	ENSP00000386100.1
	PLA2G6	ENST00000452794.5	TSL:4	n.538G>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71228 AN: 151910 Hom.: 17388 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.530 AC: 564233 AN: 1065264 Hom.: 150872 Cov.: 33 AF XY: 0.533 AC XY: 273126 AN XY: 512306

African (AFR) AF: 0.360 AC: 8022 AN: 22256

American (AMR) AF: 0.517 AC: 9989 AN: 19316

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 5747 AN: 10924

East Asian (EAS) AF: 0.276 AC: 3305 AN: 11990

South Asian (SAS) AF: 0.603 AC: 39603 AN: 65632

European-Finnish (FIN) AF: 0.478 AC: 7634 AN: 15978

Middle Eastern (MID) AF: 0.576 AC: 1375 AN: 2388

European-Non Finnish (NFE) AF: 0.534 AC: 469045 AN: 878872

Other (OTH) AF: 0.515 AC: 19513 AN: 37908

GnomAD4 genome AF: 0.469 AC: 71267 AN: 152028 Hom.: 17387 Cov.: 33 AF XY: 0.468 AC XY: 34765 AN XY: 74320

African (AFR) AF: 0.359 AC: 14882 AN: 41452

American (AMR) AF: 0.508 AC: 7757 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1811 AN: 3466

East Asian (EAS) AF: 0.290 AC: 1498 AN: 5164

South Asian (SAS) AF: 0.604 AC: 2914 AN: 4826

European-Finnish (FIN) AF: 0.458 AC: 4837 AN: 10564

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35827 AN: 67956

Other (OTH) AF: 0.491 AC: 1038 AN: 2112

Alfa AF: 0.479 Hom.: 2206

Bravo AF: 0.465

Asia WGS AF: 0.482 AC: 1680 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.50
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3788533; hg19: chr22-38523246;