3-111713937-G-T

Position:

• chr3-111713937-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000477665.2(PLCXD2):​c.675G>T​(p.Trp225Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCXD2 ENST00000477665.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.46

Genes affected

PLCXD2 (HGNC:26462): (phosphatidylinositol specific phospholipase C X domain containing 2) Predicted to enable phosphoric diester hydrolase activity. Predicted to be involved in lipid catabolic process and signal transduction. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCXD2	NM_001413064.1	c.675G>T	p.Trp225Cys	missense_variant	3/4		NP_001399993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCXD2	ENST00000477665.2	c.675G>T	p.Trp225Cys	missense_variant	3/5	1	NM_001185106.1	ENSP00000420686.1
PLCXD2	ENST00000636933.2	c.675G>T	p.Trp225Cys	missense_variant	3/4	5		ENSP00000490816.1
PLCXD2	ENST00000393934.7	c.675G>T	p.Trp225Cys	missense_variant	3/4	1		ENSP00000377511.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 28, 2024

The c.675G>T (p.W225C) alteration is located in exon 3 (coding exon 3) of the PLCXD2 gene. This alteration results from a G to T substitution at nucleotide position 675, causing the tryptophan (W) at amino acid position 225 to be replaced by a cysteine (C). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;.;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.1	.;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-13	.;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;D
Vest4		0.94, 0.94
MutPred		0.79		Loss of ubiquitination at K229 (P = 0.0957);Loss of ubiquitination at K229 (P = 0.0957);Loss of ubiquitination at K229 (P = 0.0957);
MVP		0.15
MPC		0.69
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1941234034; hg19: chr3-111432784;