Variant rs757326350 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The ENST00000266505.12(PLCZ1):c.1465A>T(p.Ile489Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLCZ1
ENST00000266505.12 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.50

Variant links:

Genes affected

PLCZ1 (HGNC:19218): (phospholipase C zeta 1) The protein encoded by this gene is a member of the phosphoinositide-specific phospholipase C family. Members in this family, classified into six isotypes that are tissue- and organ-specific, hydrolyze phosphatidylinositol 4,5-bisphosphate just before the phosphate group to yield diacylglycerol and inositol 1,4,5-trisphosphate. This protein localizes to the acrosome in spermatozoa and elicits Ca(2+) oscillations and egg activation during fertilization that leads to early embryonic development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

PLCZ1 links:

PIK3C2G (HGNC:):

PIK3C2G links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

PP5

Variant 12-18688215-T-A is Pathogenic according to our data. Variant chr12-18688215-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 271283.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-18688215-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCZ1	NM_033123.4 linkuse as main transcript	c.1465A>T	p.Ile489Phe	missense_variant	13/15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12 linkuse as main transcript	c.1465A>T	p.Ile489Phe	missense_variant	13/15	1	NM_033123.4	ENSP00000266505	P2	Q86YW0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248072

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455114

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spermatogenic failure 17

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 18, 2020

- -

PLCZ1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2022

The PLCZ1 c.1465A>T variant is predicted to result in the amino acid substitution p.Ile489Phe. This variant was reported in the homozygous state in patients with male infertility with functional studies showing this variant is deleterious, leading to the absence of the protein in sperm (Escoffier et al 2016. PubMed ID: 26721930). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-18841149-T-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

.;.;T;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.3

.;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.0

.;D;D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

.;D;D;D;D

Sift4G

Pathogenic

0.0010

.;D;D;D;.

Polyphen

1.0

.;D;D;.;.

Vest4

0.78, 0.77, 0.79

MutPred

0.61

.;.;Gain of catalytic residue at L484 (P = 0.0134);.;.;

MVP

0.83

MPC

0.079

ClinPred

1.0

GERP RS

5.7

Varity_R

0.78

gMVP

0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over