chr19-40366634-G-A

Position:

chr19-40366634-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012268.4(PLD3):c.52G>A(p.Ala18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,581,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

PLD3
NM_012268.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.826

Variant links:

Genes affected

PLD3 (HGNC:17158): (phospholipase D family member 3) This gene encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The encoded protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains. This protein influences processing of amyloid-beta precursor protein. Mutations in this gene are associated with Alzheimer disease risk. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Apr 2014]

PLD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008744985).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PLD3	NM_012268.4 linkuse as main transcript	c.52G>A	p.Ala18Thr	missense_variant	4/13	ENST00000409735.9
PLD3	NM_001031696.4 linkuse as main transcript	c.52G>A	p.Ala18Thr	missense_variant	4/13
PLD3	NM_001291311.2 linkuse as main transcript	c.52G>A	p.Ala18Thr	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD3	ENST00000409735.9 linkuse as main transcript	c.52G>A	p.Ala18Thr	missense_variant	4/13	1	NM_012268.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

226472

Hom.:

AF XY:

0.000312

AC XY:

AN XY:

121900

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 SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000581

Gnomad OTH exome

AF:

0.000186

GnomAD4 exome

AF:

0.000111

AC:

158

AN:

1429630

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

112

AN XY:

707930

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000402

Gnomad4 OTH exome

AF:

0.0000509

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 2175370). This variant has not been reported in the literature in individuals affected with PLD3-related conditions. This variant is present in population databases (rs757404195, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the PLD3 protein (p.Ala18Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.1

DANN

Benign

0.92

DEOGEN2

Benign

0.025

.;T;T;T;T;T;T;T;T;T;.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.60

T;T;T;.;.;T;.;T;.;T;T;T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.0087

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;.;.;L;L;.;L;.;L;.;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.48

.;N;.;N;N;.;N;.;N;.;.;N;N

REVEL

Benign

0.048

Sift

Benign

0.19

.;T;.;T;T;.;T;.;T;.;.;T;T

Sift4G

Pathogenic

0.0

D;T;D;T;T;D;T;D;T;D;T;T;T

Polyphen

0.13

.;.;.;B;B;.;B;.;B;.;.;B;.

Vest4

0.16, 0.27, 0.15, 0.28

MVP

0.12

MPC

0.36

ClinPred

0.015

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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