rs145999145

chr19-40371688-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 4.18

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]

ACMG classification

Verdict is Benign. Variant got -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 GnomAd at 545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD3	NM_012268.4	c.694G>A	p.Val232Met	missense_variant	9/13	ENST00000409735.9
PLD3	NM_001031696.4	c.694G>A	p.Val232Met	missense_variant	9/13
PLD3	NM_001291311.2	c.694G>A	p.Val232Met	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD3	ENST00000409735.9	c.694G>A	p.Val232Met	missense_variant	9/13	1	NM_012268.4	P1

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152130 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00315 AC: 789 AN: 250676 Hom.: 2 AF XY: 0.00328 AC XY: 445 AN XY: 135632

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 SAS exome AF: 0.000851

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.: 23 Cov.: 31 AF XY: 0.00507 AC XY: 3684 AN XY: 726792

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000824

Gnomad4 FIN exome AF: 0.00312

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00524

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74446

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.00615

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00486 Hom.: 2

Bravo AF: 0.00313

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00294 AC: 357

EpiCase AF: 0.00540

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PLD3: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

Alzheimer disease 19 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 23, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	26
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	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.9	M;M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
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	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.52

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

Other links and lift over

dbSNP: rs145999145; hg19: chr19-40877595; COSMIC: COSV100735199; COSMIC: COSV100735199;