chr3-38008466-T-G

Variant names:

• chr3-38008466-T-G
• rs773349864
• NM_006225.4:c.1894A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006225.4(PLCD1):​c.1894A>C​(p.Asn632His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. N632K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PLCD1 NM_006225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.641
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04063788).

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.1894A>C	p.Asn632His	missense	Exon 12 of 15	NP_006216.2	A0A384MR47
	PLCD1	NM_001130964.2		c.1957A>C	p.Asn653His	missense	Exon 12 of 15	NP_001124436.1	P51178-2
	PLCD1	NR_024071.2		n.2121A>C		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCD1	ENST00000334661.5	TSL:1 MANE Select	c.1894A>C	p.Asn632His	missense	Exon 12 of 15	ENSP00000335600.4	P51178-1
	PLCD1	ENST00000463876.5	TSL:2	c.1957A>C	p.Asn653His	missense	Exon 12 of 15	ENSP00000430344.1	P51178-2
	PLCD1	ENST00000956065.1		c.1891A>C	p.Asn631His	missense	Exon 12 of 15	ENSP00000626124.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251330 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112000

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.060
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.64
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.056
Sift	Benign	0.68	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.47		Gain of catalytic residue at R630 (P = 0.1496)
MVP		0.47
MPC		0.22
ClinPred		0.018	T
GERP RS		-2.8
Varity_R		0.038
gMVP		0.27
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs773349864; hg19: chr3-38049957;