22-31135830-A-C

Position:

• chr22-31135830-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015715.5(PLA2G3):​c.1423T>G​(p.Trp475Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLA2G3 NM_015715.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.33

Genes affected

PLA2G3 (HGNC:17934): (phospholipase A2 group III) This gene encodes a protein that belongs to the secreted phospholipase A2 family, whose members include the bee venom enzyme. The encoded enzyme functions in lipid metabolism and catalyzes the calcium-dependent hydrolysis of the sn-2 acyl bond of phospholipids to release arachidonic acid and lysophospholipids. This enzyme acts as a negative regulator of ciliogenesis, and may play a role in cancer development by stimulating tumor cell growth and angiogenesis. This gene is associated with oxidative stress, and polymorphisms in this gene are linked to risk for Alzheimer's disease. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066632956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G3	NM_015715.5	c.1423T>G	p.Trp475Gly	missense_variant	7/7	ENST00000215885.4	NP_056530.2
PLA2G3	XM_011530204.2	c.880T>G	p.Trp294Gly	missense_variant	7/7		XP_011528506.1
PLA2G3	XM_011530205.2	c.880T>G	p.Trp294Gly	missense_variant	7/7		XP_011528507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G3	ENST00000215885.4	c.1423T>G	p.Trp475Gly	missense_variant	7/7	1	NM_015715.5	ENSP00000215885.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Oct 01, 2024

The c.1423T>G (p.W475G) alteration is located in exon 7 (coding exon 7) of the PLA2G3 gene. This alteration results from a T to G substitution at nucleotide position 1423, causing the tryptophan (W) at amino acid position 475 to be replaced by a glycine (G). 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	0.059
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.41
DANN	Benign	0.55
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.043
Sift	Benign	0.094	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.19		Gain of phosphorylation at S477 (P = 0.1187);
MVP		0.14
MPC		0.12
ClinPred		0.038	T
GERP RS		-7.1
Varity_R		0.11
gMVP		0.26

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: rs1310508624; hg19: chr22-31531816;