chr19-40366857-G-A

Position:

chr19-40366857-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_012268.4(PLD3):c.187G>A(p.Gly63Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,613,978 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. G63G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 5 hom. )

Consequence

PLD3
NM_012268.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.07

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007906795).

BP6

Variant 19-40366857-G-A is Benign according to our data. Variant chr19-40366857-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2046591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40366857-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PLD3	NM_012268.4 linkuse as main transcript	c.187G>A	p.Gly63Ser	missense_variant	5/13	ENST00000409735.9
PLD3	NM_001031696.4 linkuse as main transcript	c.187G>A	p.Gly63Ser	missense_variant	5/13
PLD3	NM_001291311.2 linkuse as main transcript	c.187G>A	p.Gly63Ser	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD3	ENST00000409735.9 linkuse as main transcript	c.187G>A	p.Gly63Ser	missense_variant	5/13	1	NM_012268.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000868

AC:

132

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000999

AC:

251

AN:

251132

Hom.:

AF XY:

0.00106

AC XY:

144

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00736

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000925

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000737

AC:

1077

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000785

AC XY:

571

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000530

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.000861

AC:

131

AN:

152230

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000933

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PLD3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	- -

PLD3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0069

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

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.73

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

M_CAP

Benign

0.0078

MetaRNN

Benign

0.0079

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

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

MutationTaster

Benign

0.98

N;N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.070

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

REVEL

Benign

0.054

Sift

Benign

0.58

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.0

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

Vest4

0.22, 0.25, 0.22, 0.26, 0.22

MVP

0.50

MPC

0.37

ClinPred

0.0045

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.021

gMVP

0.72

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