17-45113166-G-A

Position:

• chr17-45113166-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133373.5(PLCD3):​c.2087C>T​(p.Pro696Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCD3 NM_133373.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

Genes affected

PLCD3 (HGNC:9061): (phospholipase C delta 3) This gene encodes a member of the phospholipase C family, which catalyze the hydrolysis of phosphatidylinositol 4,5-bisphosphate to generate the second messengers diacylglycerol and inositol 1,4,5-trisphosphate (IP3). Diacylglycerol and IP3 mediate a variety of cellular responses to extracellular stimuli by inducing protein kinase C and increasing cytosolic Ca(2+) concentrations. This enzyme localizes to the plasma membrane and requires calcium for activation. Its activity is inhibited by spermine, sphingosine, and several phospholipids. [provided by RefSeq, Jul 2008]

PLCD3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCD3	NM_133373.5	c.2087C>T	p.Pro696Leu	missense_variant	13/15	ENST00000619929.5	NP_588614.1
PLCD3	XM_024450554.2	c.2222C>T	p.Pro741Leu	missense_variant	13/15		XP_024306322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCD3	ENST00000619929.5	c.2087C>T	p.Pro696Leu	missense_variant	13/15	1	NM_133373.5	ENSP00000479636.1
PLCD3	ENST00000539433.1	c.200C>T	p.Pro67Leu	missense_variant	2/3	3		ENSP00000443079.1
PLCD3	ENST00000543623.5	n.394C>T		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Mar 29, 2023

The c.2087C>T (p.P696L) alteration is located in exon 13 (coding exon 13) of the PLCD3 gene. This alteration results from a C to T substitution at nucleotide position 2087, causing the proline (P) at amino acid position 696 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.82	P
Vest4		0.60
MutPred		0.67		Gain of stability (P = 0.2235);
MVP		0.65
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-43190534;