1-20086083-G-C

Variant names:

• chr1-20086083-G-C
• rs2016272356
• NM_000929.3:c.41G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000929.3(PLA2G5):​c.41G>C​(p.Ser14Thr) variant causes a missense, splice region 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. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLA2G5 NM_000929.3 missense, splice_region
• Scores: Splicing: ADA: 0.9655
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 0 publications found

Genes affected

PLA2G5 (HGNC:9038): (phospholipase A2 group V) This gene is a member of the secretory phospholipase A2 family. It is located in a tightly-linked cluster of secretory phospholipase A2 genes on chromosome 1. The encoded enzyme catalyzes the hydrolysis of membrane phospholipids to generate lysophospholipids and free fatty acids including arachidonic acid. It preferentially hydrolyzes linoleoyl-containing phosphatidylcholine substrates. Secretion of this enzyme is thought to induce inflammatory responses in neighboring cells. Alternatively spliced transcript variants have been found, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

PLA2G5 Gene-Disease associations (from GenCC):

• familial benign flecked retina

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P
• late-adult onset retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000929.3. 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
	PLA2G5	NM_000929.3	MANE Select	c.41G>C	p.Ser14Thr	missense splice_region	Exon 3 of 5	NP_000920.1	P39877

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G5	ENST00000375108.4	TSL:1 MANE Select	c.41G>C	p.Ser14Thr	missense splice_region	Exon 3 of 5	ENSP00000364249.3	P39877
	PLA2G5	ENST00000894073.1		c.41G>C	p.Ser14Thr	missense splice_region	Exon 5 of 7	ENSP00000564132.1
	PLA2G5	ENST00000894074.1		c.41G>C	p.Ser14Thr	missense splice_region	Exon 7 of 9	ENSP00000564133.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.020
Sift	Benign	0.23	T
Sift4G	Benign	0.17	T
Polyphen		0.18	B
Vest4		0.28
MutPred		0.45		Loss of sheet (P = 0.1907)
MVP		0.42
MPC		0.24
ClinPred		0.43	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.46
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.12		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: rs2016272356; hg19: chr1-20412576;