19-40371688-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_012268.4(PLD3):c.694G>A(p.Val232Met) variant causes a missense change. The variant allele was found at a frequency of 0.00501 in 1,613,184 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V232V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 23 hom. )

Consequence

PLD3
NM_012268.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 4.18

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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015966982).

BP6

Variant 19-40371688-G-A is Benign according to our data. Variant chr19-40371688-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 120224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40371688-G-A is described in Lovd as [Likely_benign]. Variant chr19-40371688-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLD3	NM_012268.4 link	c.694G>A	p.Val232Met	missense_variant	Exon 9 of 13	ENST00000409735.9	NP_036400.2	Q8IV08A0A024R0Q4
PLD3	NM_001031696.4 link	c.694G>A	p.Val232Met	missense_variant	Exon 9 of 13		NP_001026866.1	Q8IV08A0A024R0Q4
PLD3	NM_001291311.2 link	c.694G>A	p.Val232Met	missense_variant	Exon 9 of 13		NP_001278240.1	Q8IV08A0A024R0Q4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLD3	ENST00000409735.9 link	c.694G>A	p.Val232Met	missense_variant	Exon 9 of 13	1	NM_012268.4	ENSP00000386938.3		Q8IV08

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

545

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00615

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00315

AC:

789

AN:

250676

AF XY:

0.00328

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.00510

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00516

AC:

7533

AN:

1460934

Hom.:

Cov.:

AF XY:

0.00507

AC XY:

3684

AN XY:

726792

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33462

American (AMR)

AF:

0.00210

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000824

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00312

AC:

166

AN:

53128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00616

AC:

6848

AN:

1111470

Other (OTH)

AF:

0.00524

AC:

316

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

355

709

1064

1418

1773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00358

AC:

545

AN:

152250

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41564

American (AMR)

AF:

0.00242

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00368

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00615

AC:

418

AN:

68010

Other (OTH)

AF:

0.00332

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00456

Hom.:

Bravo

AF:

0.00313

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00294

AC:

357

EpiCase

AF:

0.00540

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLD3: BS1, BS2 -

Alzheimer disease 19

Uncertain:1

Jan 23, 2014

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;T;T;T

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

.;.;.;.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.9

M;M;M;M;M

PhyloP100

4.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.015

D;D;D;D;D

Sift4G

Uncertain

0.022

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.66

MVP

0.72

MPC

1.1

ClinPred

0.047

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.52

Mutation Taster

=100/0

polymorphism

(source)

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

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19-40371688-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over