chr19-40366785-G-A

Position:

• chr19-40366785-G-A

Variant summary

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

The NM_012268.4(PLD3):​c.115G>A​(p.Val39Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLD3 NM_012268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD3	NM_012268.4	c.115G>A	p.Val39Ile	missense_variant	5/13	ENST00000409735.9
PLD3	NM_001031696.4	c.115G>A	p.Val39Ile	missense_variant	5/13
PLD3	NM_001291311.2	c.115G>A	p.Val39Ile	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD3	ENST00000409735.9	c.115G>A	p.Val39Ile	missense_variant	5/13	1	NM_012268.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.115G>A (p.V39I) alteration is located in exon 5 (coding exon 3) of the PLD3 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the valine (V) at amino acid position 39 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0095	.;T;T;T;T;T;T;T;T;.;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T;.;.;T;.;T;.;T;T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.099	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.74	.;.;N;N;.;N;.;N;.;.;N;.
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.23	.;N;N;N;.;N;.;N;.;.;N;N
REVEL	Benign	0.051
Sift	Benign	1.0	.;T;T;T;.;T;.;T;.;.;T;T
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;D;T;D;T;T;T
Polyphen		0.024	.;.;B;B;.;B;.;B;.;.;B;.
Vest4		0.34, 0.39, 0.35, 0.40, 0.35
MutPred		0.17		Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);Gain of methylation at K35 (P = 0.0884);
MVP		0.32
MPC		0.31
ClinPred		0.54	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.030
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2078934887; hg19: chr19-40872692;