3-38007819-T-C

Variant names:

• chr3-38007819-T-C
• rs140941118
• NM_006225.4:c.2225A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_006225.4(PLCD1):​c.2225A>G​(p.Gln742Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PLCD1 NM_006225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.687
• Publications: 0 publications found

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]

PLCD1 Gene-Disease associations (from GenCC):

• nonsyndromic congenital nail disorder 3

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052479506).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000998 (152/152356) while in subpopulation AFR AF = 0.00346 (144/41586). AF 95% confidence interval is 0.003. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006225.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCD1	NM_006225.4	MANE Select	c.2225A>G	p.Gln742Arg	missense	Exon 15 of 15	NP_006216.2	A0A384MR47
	PLCD1	NM_001130964.2		c.2288A>G	p.Gln763Arg	missense	Exon 15 of 15	NP_001124436.1	P51178-2
	PLCD1	NR_024071.2		n.2452A>G		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCD1	ENST00000334661.5	TSL:1 MANE Select	c.2225A>G	p.Gln742Arg	missense	Exon 15 of 15	ENSP00000335600.4	P51178-1
	PLCD1	ENST00000463876.5	TSL:2	c.2288A>G	p.Gln763Arg	missense	Exon 15 of 15	ENSP00000430344.1	P51178-2
	PLCD1	ENST00000956065.1		c.2222A>G	p.Gln741Arg	missense	Exon 15 of 15	ENSP00000626124.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000340 AC: 85 AN: 249782 AF XY: 0.000215

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000963 AC XY: 70 AN XY: 727240

African (AFR) AF: 0.00445 AC: 149 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111996

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74508

African (AFR) AF: 0.00346 AC: 144 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000331 Hom.: 1

Bravo AF: 0.00116

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.69
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.0080
Sift	Benign	0.22	T
Sift4G	Benign	0.52	T
Polyphen		0.0040	B
Vest4		0.27
MVP		0.34
MPC		0.23
ClinPred		0.0036	T
GERP RS		2.5
Varity_R		0.043
gMVP		0.32
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs140941118; hg19: chr3-38049310;