chr16-68249385-A-G

Position:

• chr16-68249385-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012320.4(PLA2G15):​c.223A>G​(p.Ile75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PLA2G15 NM_012320.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

Genes affected

PLA2G15 (HGNC:17163): (phospholipase A2 group XV) Lysophospholipases are enzymes that act on biological membranes to regulate the multifunctional lysophospholipids. The protein encoded by this gene hydrolyzes lysophosphatidylcholine to glycerophosphorylcholine and a free fatty acid. This enzyme is present in the plasma and thought to be associated with high-density lipoprotein. A later paper contradicts the function of this gene. It demonstrates that this gene encodes a lysosomal enzyme instead of a lysophospholipase and has both calcium-independent phospholipase A2 and transacylase activities. [provided by RefSeq, Jul 2008]

PLA2G15 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34253722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G15	NM_012320.4	c.223A>G	p.Ile75Val	missense_variant	2/6	ENST00000219345.10	NP_036452.1
PLA2G15	NM_001363551.2	c.223A>G	p.Ile75Val	missense_variant	2/6		NP_001350480.1
PLA2G15	XM_011522979.3	c.223A>G	p.Ile75Val	missense_variant	2/7		XP_011521281.1
PLA2G15	XM_011522980.4	c.223A>G	p.Ile75Val	missense_variant	2/7		XP_011521282.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G15	ENST00000219345.10	c.223A>G	p.Ile75Val	missense_variant	2/6	1	NM_012320.4	ENSP00000219345.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.223A>G (p.I75V) alteration is located in exon 2 (coding exon 2) of the PLA2G15 gene. This alteration results from a A to G substitution at nucleotide position 223, causing the isoleucine (I) at amino acid position 75 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;D;T;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.66	.;N;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.98	N;N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.027	D;D;D;D;D
Sift4G	Uncertain	0.044	D;T;T;T;T
Polyphen		0.021, 0.29	.;B;.;B;.
Vest4		0.18, 0.21
MutPred		0.65		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP		0.33
MPC		0.35
ClinPred		0.61	D
GERP RS		3.5
Varity_R		0.24
gMVP		0.63

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: rs1435697637; hg19: chr16-68283288;