22-38169424-C-T

Position:

• chr22-38169424-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_003560.4(PLA2G6):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000205 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003560.4 (PLA2G6) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.3G>A	p.Met1?	start_lost	2/17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.3G>A	p.Met1?	start_lost	2/17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250760 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461620 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.;.;.;T;T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;.;.;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
PROVEAN	Benign	-1.6	N;N;N;N;N;D;D;D;D;.
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;P;P;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);
MVP		0.89
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.81
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs764959600; hg19: chr22-38565431;