19-282753-G-T

Variant names:

• chr19-282753-G-T
• rs1138439
• NM_003712.4:c.539C>A

Variant summary

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

The NM_003712.4(PLPP2):​c.539C>A​(p.Ala180Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PLPP2 NM_003712.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004555
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19
• Publications: 31 publications found

Genes affected

PLPP2 (HGNC:9230): (phospholipid phosphatase 2) The protein encoded by this gene is a member of the phosphatidic acid phosphatase (PAP) family. PAPs convert phosphatidic acid to diacylglycerol, and function in de novo synthesis of glycerolipids as well as in receptor-activated signal transduction mediated by phospholipase D. This protein is similar to phosphatidic acid phosphatase type 2A (PPAP2A) and type 2B (PPAP2B). All three proteins contain 6 transmembrane regions, and a consensus N-glycosylation site. This protein has been shown to possess membrane associated PAP activity. Three alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003712.4. 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
	PLPP2	NM_003712.4	MANE Select	c.539C>A	p.Ala180Glu	missense splice_region	Exon 4 of 6	NP_003703.1	O43688-1
	PLPP2	NM_177543.3		c.602C>A	p.Ala201Glu	missense splice_region	Exon 4 of 6	NP_808211.1	O43688-2
	PLPP2	NM_177526.3		c.371C>A	p.Ala124Glu	missense splice_region	Exon 4 of 6	NP_803545.1	O43688-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLPP2	ENST00000434325.7	TSL:1 MANE Select	c.539C>A	p.Ala180Glu	missense splice_region	Exon 4 of 6	ENSP00000388565.2	O43688-1
	PLPP2	ENST00000327790.7	TSL:5	c.602C>A	p.Ala201Glu	missense splice_region	Exon 4 of 6	ENSP00000329697.1	O43688-2
	PLPP2	ENST00000951587.1		c.539C>A	p.Ala180Glu	missense splice_region	Exon 4 of 7	ENSP00000621646.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.15	D
PhyloP100		6.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.43	B
Vest4		0.84
MutPred		0.70		Loss of MoRF binding (P = 0.0577)
MVP		0.76
MPC		0.72
ClinPred		0.99	D
GERP RS		-0.069
Varity_R		0.93
gMVP		0.96
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.12
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: rs1138439; hg19: chr19-282753;