19-812752-C-T

Variant names:

• chr19-812752-C-T
• rs1327844608
• NM_001270366.2:c.1975G>A

Variant summary

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

The NM_001270366.2(PLPPR3):​c.1975G>A​(p.Val659Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000647 in 926,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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: 0.0000065 (0 hom.)
• Consequence: PLPPR3 NM_001270366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.500

Genes affected

PLPPR3 (HGNC:23497): (phospholipid phosphatase related 3) The proteins in the lipid phosphate phosphatase (LPP) family, including PRG2, are integral membrane proteins that modulate bioactive lipid phosphates including phosphatidate, lysophosphatidate, and sphingosine-1-phosphate in the context of cell migration, neurite retraction, and mitogenesis (Brauer et al., 2003 [PubMed 12730698]).[supplied by OMIM, Mar 2008]

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=0.038561583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPPR3	NM_001270366.2	c.1975G>A	p.Val659Ile	missense_variant	Exon 8 of 8	ENST00000520876.8	NP_001257295.1
PLPPR3	NM_024888.3	c.2059G>A	p.Val687Ile	missense_variant	Exon 7 of 7		NP_079164.1
PLPPR3	XM_011528317.4	c.2059G>A	p.Val687Ile	missense_variant	Exon 7 of 7		XP_011526619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPPR3	ENST00000520876.8	c.1975G>A	p.Val659Ile	missense_variant	Exon 8 of 8	1	NM_001270366.2	ENSP00000430297.1
PLPPR3	ENST00000359894.6	c.2059G>A	p.Val687Ile	missense_variant	Exon 7 of 7	1		ENSP00000352962.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000647 AC: 6 AN: 926904 Hom.: 0 Cov.: 35 AF XY: 0.00000921 AC XY: 4 AN XY: 434406

Gnomad4 AFR exome AF: 0.0000578

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000610

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2059G>A (p.V687I) alteration is located in exon 7 (coding exon 6) of the PLPPR3 gene. This alteration results from a G to A substitution at nucleotide position 2059, causing the valine (V) at amino acid position 687 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.087
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.010	B;B
Vest4		0.10
MutPred		0.19		.;Loss of glycosylation at T663 (P = 0.1929);
MVP		0.23
MPC		1.0
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.062
gMVP		0.10

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: rs1327844608; hg19: chr19-812752;