Genetic Variant PLPPR3:p.Ala464Asp (chr19-813336-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001270366.2(PLPPR3):c.1391C>A(p.Ala464Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 1,321,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A464V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

PLPPR3
NM_001270366.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.261

Variant links:

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]

PLPPR3 links:

MIR3187 (HGNC:38319): (microRNA 3187) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR3187 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0799475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPPR3	NM_001270366.2 link	c.1391C>A	p.Ala464Asp	missense_variant	Exon 8 of 8	ENST00000520876.8	NP_001257295.1	Q6T4P5-1
PLPPR3	NM_024888.3 link	c.1475C>A	p.Ala492Asp	missense_variant	Exon 7 of 7		NP_079164.1	Q6T4P5-3
PLPPR3	XM_011528317.4 link	c.1475C>A	p.Ala492Asp	missense_variant	Exon 7 of 7		XP_011526619.1	Q6T4P5-3
MIR3187	NR_036154.1 link	n.-248G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPPR3	ENST00000520876.8 link	c.1391C>A	p.Ala464Asp	missense_variant	Exon 8 of 8	1	NM_001270366.2	ENSP00000430297.1		Q6T4P5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

77226

AF XY:

0.0000235

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000332

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000227

AC:

AN:

1321518

Hom.:

Cov.:

AF XY:

0.00000308

AC XY:

AN XY:

649116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27694

American (AMR)

AF:

0.00

AC:

AN:

24758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21108

East Asian (EAS)

AF:

0.00

AC:

AN:

33562

South Asian (SAS)

AF:

0.00

AC:

AN:

69530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3974

European-Non Finnish (NFE)

AF:

0.00000285

AC:

AN:

1053744

Other (OTH)

AF:

0.00

AC:

AN:

54928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.022

.;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.26

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.065

Sift

Benign

0.20

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.47

P;B

Vest4

0.23

MutPred

0.23

.;Gain of relative solvent accessibility (P = 0.005);

MVP

0.16

MPC

0.99

ClinPred

0.15

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.13

gMVP

0.33

Mutation Taster

=93/7

polymorphism

(source)

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

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19-813336-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over