19-40366610-C-G

Position:

• chr19-40366610-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012268.4(PLD3):​c.28C>G​(p.Leu10Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLD3 NM_012268.4 missense, splice_region
• Scores: Splicing: ADA: 0.1214
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1759775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD3	NM_012268.4	c.28C>G	p.Leu10Val	missense_variant, splice_region_variant	4/13	ENST00000409735.9
PLD3	NM_001031696.4	c.28C>G	p.Leu10Val	missense_variant, splice_region_variant	4/13
PLD3	NM_001291311.2	c.28C>G	p.Leu10Val	missense_variant, splice_region_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD3	ENST00000409735.9	c.28C>G	p.Leu10Val	missense_variant, splice_region_variant	4/13	1	NM_012268.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the PLD3 protein (p.Leu10Val). This variant has not been reported in the literature in individuals affected with PLD3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	.;T;T;T;T;T;T;T;T;T;.;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;T;T;.;.;T;.;T;.;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	.;.;.;L;L;.;L;.;L;.;.;L;.
MutationTaster	Benign	0.84	N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.020	.;N;.;N;N;.;N;.;N;.;.;N;N
REVEL	Benign	0.050
Sift	Benign	0.031	.;D;.;D;D;.;D;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;T;D;T;T;D;T;D;T;D;T;T;T
Polyphen		0.96	.;.;.;P;P;.;P;.;P;.;.;P;.
Vest4		0.37, 0.38, 0.37, 0.40
MutPred		0.14		Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);Gain of MoRF binding (P = 0.0859);
MVP		0.56
MPC		0.65
ClinPred		0.66	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.0		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: rs2078928651; hg19: chr19-40872517;