22-38132881-C-T

Variant names:

• chr22-38132881-C-T
• rs11570680
• NM_003560.4:c.1027G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003560.4(PLA2G6):​c.1027G>A​(p.Ala343Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,553,716 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A343V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0092 (6 hom., cov: 33)
  • Exomes 𝑓: 0.012 (136 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.26
• 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, 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003560.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031460226).
• BP6: Variant 22-38132881-C-T is Benign according to our data. Variant chr22-38132881-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00918 (1399/152360) while in subpopulation SAS AF = 0.0153 (74/4828). AF 95% confidence interval is 0.0125. There are 6 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1027G>A	p.Ala343Thr	missense	Exon 7 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.1027G>A	p.Ala343Thr	missense	Exon 7 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.1027G>A	p.Ala343Thr	missense	Exon 7 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.1027G>A	p.Ala343Thr	missense	Exon 7 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.1027G>A	p.Ala343Thr	missense	Exon 7 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.1027G>A	p.Ala343Thr	missense	Exon 7 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1401 AN: 152242 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0110 AC: 1757 AN: 159972 AF XY: 0.0121

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.00577

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0121 AC: 16997 AN: 1401356 Hom.: 136 Cov.: 31 AF XY: 0.0125 AC XY: 8670 AN XY: 691800

African (AFR) AF: 0.00205 AC: 65 AN: 31776

American (AMR) AF: 0.00645 AC: 234 AN: 36306

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 438 AN: 25180

East Asian (EAS) AF: 0.000139 AC: 5 AN: 36008

South Asian (SAS) AF: 0.0158 AC: 1253 AN: 79478

European-Finnish (FIN) AF: 0.00716 AC: 340 AN: 47462

Middle Eastern (MID) AF: 0.0289 AC: 160 AN: 5528

European-Non Finnish (NFE) AF: 0.0128 AC: 13823 AN: 1081474

Other (OTH) AF: 0.0117 AC: 679 AN: 58144

GnomAD4 genome AF: 0.00918 AC: 1399 AN: 152360 Hom.: 6 Cov.: 33 AF XY: 0.00938 AC XY: 699 AN XY: 74514

African (AFR) AF: 0.00212 AC: 88 AN: 41590

American (AMR) AF: 0.00888 AC: 136 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4828

European-Finnish (FIN) AF: 0.00715 AC: 76 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 894 AN: 68030

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.0128 Hom.: 32

Bravo AF: 0.00952

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00208 AC: 9

ESP6500EA AF: 0.0128 AC: 109

ExAC AF: 0.00664 AC: 750

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
-	-	1	Infantile neuroaxonal dystrophy (1)
-	-	1	Parkinson disease;C0242422:Parkinsonian disorder;C0393568:Vascular parkinsonism (1)
-	-	1	PLA2G6-associated neurodegeneration (1)
-	-	1	PLA2G6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.37	N
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.021
Sift	Benign	0.30	T
Sift4G	Benign	0.31	T
Polyphen		0.032	B
Vest4		0.12
MPC		0.26
ClinPred		0.017	T
GERP RS		3.1
Varity_R		0.052
gMVP		0.76
Mutation Taster		=90/10	polymorphism

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: rs11570680; hg19: chr22-38528888; COSMIC: COSV108126072; COSMIC: COSV108126072;