dbSNP rs201896370: PLCD4:p.Arg98Ser (chr2-218618689-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032726.4(PLCD4):c.292C>A(p.Arg98Ser) 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 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R98C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLCD4
NM_032726.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.97

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCD4	NM_032726.4 link	c.292C>A	p.Arg98Ser	missense_variant	Exon 4 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.292C>A	p.Arg98Ser	missense_variant	Exon 4 of 16	1	NM_032726.4	ENSP00000388631.2	Q9BRC7-1
PLCD4	ENST00000432688.5 link	c.292C>A	p.Arg98Ser	missense_variant	Exon 4 of 17	5		ENSP00000396185.1	C9JEA7
PLCD4	ENST00000417849.5 link	c.292C>A	p.Arg98Ser	missense_variant	Exon 4 of 17	5		ENSP00000396942.1	Q9BRC7-1
PLCD4	ENST00000444453.5 link	n.189C>A		non_coding_transcript_exon_variant	Exon 4 of 5	4		ENSP00000415725.1	F2Z3H8
PLCD4	ENST00000446503.5 link	n.189C>A		non_coding_transcript_exon_variant	Exon 4 of 6	4		ENSP00000406040.1	F2Z3H8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111826

Other (OTH)

AF:

0.00

AC:

AN:

60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D;.;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;.;D;D

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

-0.028

MutationAssessor

Uncertain

2.3

M;M;.;.

PhyloP100

3.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.020

D;D;D;D

Sift4G

Uncertain

0.053

T;T;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.62

MutPred

0.76

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.84

MPC

0.88

ClinPred

0.99

GERP RS

4.9

Varity_R

0.68

gMVP

0.53

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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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rs201896370

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