3-111708279-C-T

Position:

• chr3-111708279-C-T

Variant summary

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

The ENST00000477665.2(PLCXD2):​c.517C>T​(p.His173Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCXD2 ENST00000477665.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCXD2	NM_001413064.1	c.517C>T	p.His173Tyr	missense_variant	2/4	ENST00000636933.2	NP_001399993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCXD2	ENST00000636933.2	c.517C>T	p.His173Tyr	missense_variant	2/4	5	NM_001413064.1	ENSP00000490816	P1
PLCXD2	ENST00000477665.2	c.517C>T	p.His173Tyr	missense_variant	2/5	1		ENSP00000420686
PLCXD2	ENST00000393934.7	c.517C>T	p.His173Tyr	missense_variant	2/4	1		ENSP00000377511
PLCXD2	ENST00000468174.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 28, 2022

The c.517C>T (p.H173Y) alteration is located in exon 2 (coding exon 2) of the PLCXD2 gene. This alteration results from a C to T substitution at nucleotide position 517, causing the histidine (H) at amino acid position 173 to be replaced by a tyrosine (Y). 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	0.89
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	.;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.8	.;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.046	.;D;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.89, 0.89
MutPred		0.90		Loss of ubiquitination at K174 (P = 0.1322);Loss of ubiquitination at K174 (P = 0.1322);Loss of ubiquitination at K174 (P = 0.1322);
MVP		0.30
MPC		0.59
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.74

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-111427126;