Genetic Variant PLPPR3:p.Ala676Ser (chr19-812701-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001270366.2(PLPPR3):c.2026G>T(p.Ala676Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,051,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. A676E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PLPPR3
NM_001270366.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.389

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:

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ACMG classification

Classification made for transcript

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=0.044363797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPPR3	NM_001270366.2 link	c.2026G>T	p.Ala676Ser	missense_variant	Exon 8 of 8	ENST00000520876.8	NP_001257295.1	Q6T4P5-1
PLPPR3	NM_024888.3 link	c.2110G>T	p.Ala704Ser	missense_variant	Exon 7 of 7		NP_079164.1	Q6T4P5-3
PLPPR3	XM_011528317.4 link	c.2110G>T	p.Ala704Ser	missense_variant	Exon 7 of 7		XP_011526619.1	Q6T4P5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPPR3	ENST00000520876.8 link	c.2026G>T	p.Ala676Ser	missense_variant	Exon 8 of 8	1	NM_001270366.2	ENSP00000430297.1		Q6T4P5-1
PLPPR3	ENST00000359894.6 link	c.2110G>T	p.Ala704Ser	missense_variant	Exon 7 of 7	1		ENSP00000352962.2		Q6T4P5-3

Frequencies

GnomAD3 genomes

AF:

0.0000409

AC:

AN:

146766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000677

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000758

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000232

AC:

AN:

904564

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

423036

show subpopulations

Gnomad4 AFR exome

AF:

0.0000593

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:

0.0000223

Gnomad4 OTH exome

AF:

0.0000320

GnomAD4 genome

AF:

0.0000409

AC:

AN:

146766

Hom.:

Cov.:

AF XY:

0.0000560

AC XY:

AN XY:

71386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000677

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000758

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2110G>T (p.A704S) alteration is located in exon 7 (coding exon 6) of the PLPPR3 gene. This alteration results from a G to T substitution at nucleotide position 2110, causing the alanine (A) at amino acid position 704 to be replaced by a serine (S). 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

0.075

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.0

DANN

Benign

0.96

DEOGEN2

Benign

0.010

.;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.37

N;N

REVEL

Benign

0.079

Sift

Benign

1.0

T;T

Sift4G

Benign

0.89

T;T

Polyphen

0.073

B;B

Vest4

0.12

MutPred

0.10

.;Gain of glycosylation at A676 (P = 0.0095);

MVP

0.17

MPC

0.37

ClinPred

0.17

GERP RS

3.6

Varity_R

0.074

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over