3-38008261-C-T

Position:

• chr3-38008261-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_006225.4(PLCD1):​c.2009G>A​(p.Arg670His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,614,022 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R670C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PLCD1 NM_006225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013650209).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000248 (362/1461778) while in subpopulation MID AF= 0.00329 (19/5768). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4_exome. There are 183 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCD1	NM_006225.4	c.2009G>A	p.Arg670His	missense_variant	13/15	ENST00000334661.5
PLCD1	NM_001130964.2	c.2072G>A	p.Arg691His	missense_variant	13/15
PLCD1	NR_024071.2	n.2236G>A		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCD1	ENST00000334661.5	c.2009G>A	p.Arg670His	missense_variant	13/15	1	NM_006225.4	A1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251346 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1461778 Hom.: 0 Cov.: 33 AF XY: 0.000252 AC XY: 183 AN XY: 727202

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000715 Hom.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000237

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

Oct 21, 2021

The c.2072G>A (p.R691H) alteration is located in exon 13 (coding exon 13) of the PLCD1 gene. This alteration results from a G to A substitution at nucleotide position 2072, causing the arginine (R) at amino acid position 691 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	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.47	.;N
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.11
Sift	Benign	0.042	D;T
Sift4G	Uncertain	0.015	D;D
Polyphen		0.0030	.;B
Vest4		0.095
MVP		0.69
MPC		0.27
ClinPred		0.031	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.42

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: rs139342994; hg19: chr3-38049752;