rs4819

chr19-40378026-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012268.4(PLD3):c.1326G>A(p.Ala442=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,613,498 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 32)
  • Exomes 𝑓: 0.016 (215 hom.)
• Consequence: PLD3 NM_012268.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.66

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-40378026-G-A is Benign according to our data. Variant chr19-40378026-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 403325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40378026-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0132 (2003/152238) while in subpopulation AMR AF= 0.0267 (408/15294). AF 95% confidence interval is 0.0245. There are 27 homozygotes in gnomad4. There are 1004 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2000 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD3	NM_012268.4	c.1326G>A	p.Ala442=	synonymous_variant	13/13	ENST00000409735.9
PLD3	NM_001031696.4	c.1326G>A	p.Ala442=	synonymous_variant	13/13
PLD3	NM_001291311.2	c.1326G>A	p.Ala442=	synonymous_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD3	ENST00000409735.9	c.1326G>A	p.Ala442=	synonymous_variant	13/13	1	NM_012268.4	P1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 2000 AN: 152120 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0133 AC: 3327 AN: 250520 Hom.: 41 AF XY: 0.0133 AC XY: 1796 AN XY: 135414

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00533

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.00743

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0159 AC: 23175 AN: 1461260 Hom.: 215 Cov.: 34 AF XY: 0.0154 AC XY: 11219 AN XY: 726924

Gnomad4 AFR exome AF: 0.00433

Gnomad4 AMR exome AF: 0.0217

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00395

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00846

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0132 AC: 2003 AN: 152238 Hom.: 27 Cov.: 32 AF XY: 0.0135 AC XY: 1004 AN XY: 74440

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0138 Hom.: 9

Bravo AF: 0.0129

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0146

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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	Feb 01, 2024	PLD3: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency. OB 12/23/15: 1.4% in Eur chr, 14 hom in ExAC -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	10
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs4819; hg19: chr19-40883933; COSMIC: COSV52524912; COSMIC: COSV52524912;