12-18688215-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_033123.4(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 NM_033123.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.50

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]

PIK3C2G (HGNC:):

ACMG classification

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	UniProt
PLCZ1	NM_033123.4	c.1465A>T	p.Ile489Phe	missense_variant	13/15	ENST00000266505.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1465A>T	p.Ile489Phe	missense_variant	13/15	1	NM_033123.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248072 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134396

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: 3 AN: 1455114 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724212

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
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	D
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

Other links and lift over

dbSNP: rs757326350; hg19: chr12-18841149;