Genetic Variant PLCD4:p.Arg25Leu (chr2-218615955-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032726.4(PLCD4):c.74G>T(p.Arg25Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PLCD4
NM_032726.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.68

Publications

0 publications found

Variant links:

Genes affected

PLCD4 (HGNC:9062): (phospholipase C delta 4) This gene encodes a member of the delta class of phospholipase C enzymes. Phospholipase C enzymes play a critical role in many cellular processes by hydrolyzing phosphatidylinositol 4,5-bisphosphate into two intracellular second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. Expression of this gene may be a marker for cancer. [provided by RefSeq, Jan 2011]

PLCD4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCD4	NM_032726.4 link	c.74G>T	p.Arg25Leu	missense_variant	Exon 3 of 16	ENST00000450993.7	NP_116115.1	Q9BRC7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLCD4	ENST00000450993.7 link	c.74G>T	p.Arg25Leu	missense_variant	Exon 3 of 16	1	NM_032726.4	ENSP00000388631.2	Q9BRC7-1
PLCD4	ENST00000432688.5 link	c.74G>T	p.Arg25Leu	missense_variant	Exon 3 of 17	5		ENSP00000396185.1	C9JEA7
PLCD4	ENST00000417849.5 link	c.74G>T	p.Arg25Leu	missense_variant	Exon 3 of 17	5		ENSP00000396942.1	Q9BRC7-1
PLCD4	ENST00000444453.5 link	n.74G>T		non_coding_transcript_exon_variant	Exon 3 of 5	4		ENSP00000415725.1	F2Z3H8
PLCD4	ENST00000446503.5 link	n.74G>T		non_coding_transcript_exon_variant	Exon 3 of 6	4		ENSP00000406040.1	F2Z3H8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111868

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0073

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.17

T;T;.;T

Eigen

Benign

0.067

Eigen_PC

Benign

0.061

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.70

T;.;T;T

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.47

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.2

L;L;.;.

PhyloP100

7.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.66

T;T;D;T

Polyphen

1.0

D;D;.;.

Vest4

0.77

MutPred

0.58

Loss of methylation at K30 (P = 0.0273);Loss of methylation at K30 (P = 0.0273);Loss of methylation at K30 (P = 0.0273);Loss of methylation at K30 (P = 0.0273);

MVP

0.69

MPC

0.93

ClinPred

0.97

GERP RS

3.2

Varity_R

0.073

gMVP

0.76

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-218615955-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over