chr3-38008065-T-G

Position:

• chr3-38008065-T-G

Variant summary

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

The NM_006225.4(PLCD1):​c.2134A>C​(p.Lys712Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLCD1 NM_006225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

Genes affected

PLCD1 (HGNC:9060): (phospholipase C delta 1) This gene encodes a member of the phospholipase C family. Phospholipase C isozymes play critical roles in intracellular signal transduction by catalyzing the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). The encoded protein functions as a tumor suppressor in several types of cancer, and mutations in this gene are a cause of hereditary leukonychia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

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=0.2616077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCD1	NM_006225.4	c.2134A>C	p.Lys712Gln	missense_variant	14/15	ENST00000334661.5
PLCD1	NM_001130964.2	c.2197A>C	p.Lys733Gln	missense_variant	14/15
PLCD1	NR_024071.2	n.2361A>C		non_coding_transcript_exon_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCD1	ENST00000334661.5	c.2134A>C	p.Lys712Gln	missense_variant	14/15	1	NM_006225.4	A1
PLCD1	ENST00000463876.5	c.2197A>C	p.Lys733Gln	missense_variant	14/15	2		P3
PLCD1	ENST00000417185.6	n.271A>C		non_coding_transcript_exon_variant	1/2	2
PLCD1	ENST00000461445.5	n.2857A>C		non_coding_transcript_exon_variant	11/12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 21, 2023

The c.2197A>C (p.K733Q) alteration is located in exon 14 (coding exon 14) of the PLCD1 gene. This alteration results from a A to C substitution at nucleotide position 2197, causing the lysine (K) at amino acid position 733 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.19	.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	0.50	D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.15
Sift	Benign	0.26	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.24	.;B
Vest4		0.20
MutPred		0.52		.;Loss of methylation at K712 (P = 0.02);
MVP		0.66
MPC		0.31
ClinPred		0.40	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1435734980; hg19: chr3-38049556;