chr22-38143034-T-C

Variant names:

• chr22-38143034-T-C
• rs4375
• NM_003560.4:c.609+71A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003560.4(PLA2G6):​c.609+71A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,433,638 control chromosomes in the GnomAD database, including 148,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18628 hom., cov: 31)
  • Exomes 𝑓: 0.44 (129618 hom.)
• Consequence: PLA2G6 NM_003560.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.499
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-38143034-T-C is Benign according to our data. Variant chr22-38143034-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.609+71A>G		intron_variant	Intron 4 of 16	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.609+71A>G		intron_variant	Intron 4 of 16	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73621 AN: 151794 Hom.: 18612 Cov.: 31

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.475

GnomAD4 exome AF: 0.445 AC: 570260 AN: 1281726 Hom.: 129618 Cov.: 18 AF XY: 0.449 AC XY: 290189 AN XY: 646784

African (AFR) AF: 0.617 AC: 18510 AN: 29988

American (AMR) AF: 0.480 AC: 21357 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 11618 AN: 25076

East Asian (EAS) AF: 0.272 AC: 10574 AN: 38828

South Asian (SAS) AF: 0.555 AC: 45809 AN: 82476

European-Finnish (FIN) AF: 0.396 AC: 20513 AN: 51844

Middle Eastern (MID) AF: 0.538 AC: 2943 AN: 5474

European-Non Finnish (NFE) AF: 0.436 AC: 414160 AN: 949048

Other (OTH) AF: 0.455 AC: 24776 AN: 54492

GnomAD4 genome AF: 0.485 AC: 73692 AN: 151912 Hom.: 18628 Cov.: 31 AF XY: 0.484 AC XY: 35957 AN XY: 74240

African (AFR) AF: 0.607 AC: 25170 AN: 41456

American (AMR) AF: 0.490 AC: 7469 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1619 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1491 AN: 5148

South Asian (SAS) AF: 0.564 AC: 2714 AN: 4808

European-Finnish (FIN) AF: 0.388 AC: 4090 AN: 10544

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29470 AN: 67934

Other (OTH) AF: 0.478 AC: 1005 AN: 2104

Alfa AF: 0.460 Hom.: 2763

Bravo AF: 0.494

Asia WGS AF: 0.480 AC: 1673 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		-0.50
PromoterAI		-0.00040	Neutral
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: rs4375; hg19: chr22-38539041; COSMIC: COSV59268338; COSMIC: COSV59268338;