chr17-45115189-C-T

Position:

• chr17-45115189-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133373.5(PLCD3):​c.1616G>A​(p.Arg539His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,584,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: PLCD3 NM_133373.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.131

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017055392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCD3	NM_133373.5	c.1616G>A	p.Arg539His	missense_variant	10/15	ENST00000619929.5	NP_588614.1
PLCD3	XM_024450554.2	c.1616G>A	p.Arg539His	missense_variant	10/15		XP_024306322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCD3	ENST00000619929.5	c.1616G>A	p.Arg539His	missense_variant	10/15	1	NM_133373.5	ENSP00000479636.1
PLCD3	ENST00000611986.1	n.379G>A		non_coding_transcript_exon_variant	3/4	5
PLCD3	ENST00000615898.4	n.91G>A		non_coding_transcript_exon_variant	2/4	3
PLCD3	ENST00000618022.4	n.155G>A		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000378 AC: 76 AN: 200886 Hom.: 1 AF XY: 0.000359 AC XY: 39 AN XY: 108636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00386

Gnomad EAS exome AF: 0.000717

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000286

Gnomad OTH exome AF: 0.000397

GnomAD4 exome AF: 0.000316 AC: 453 AN: 1432698 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 229 AN XY: 709902

Gnomad4 AFR exome AF: 0.000212

Gnomad4 AMR exome AF: 0.0000741

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.000285

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.000389

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74436

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000342 Hom.: 1

Bravo AF: 0.000230

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000596 AC: 5

ExAC AF: 0.000267 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Sep 22, 2022

The c.1616G>A (p.R539H) alteration is located in exon 10 (coding exon 10) of the PLCD3 gene. This alteration results from a G to A substitution at nucleotide position 1616, causing the arginine (R) at amino acid position 539 to be replaced by a histidine (H). 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	0.086
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Benign	0.16
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.89	T
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.33	T
Polyphen		0.99	D
Vest4		0.35
MVP		0.51
ClinPred		0.065	T
GERP RS		0.53
Varity_R		0.070
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs199969953; hg19: chr17-43192556; COSMIC: COSV59562620; COSMIC: COSV59562620;