chr12-18699913-A-G

Position:

chr12-18699913-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting

The NM_033123.4(PLCZ1):c.1055T>C(p.Leu352Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,612,104 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PLCZ1
NM_033123.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.36

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:8973): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma) The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

PIK3C2G links:

PLCZ1 (HGNC:):

PLCZ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000151 (22/1459934) while in subpopulation AMR AF= 0.00047 (21/44678). AF 95% confidence interval is 0.000314. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCZ1	NM_033123.4 linkuse as main transcript	c.1055T>C	p.Leu352Pro	missense_variant	10/15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLCZ1	ENST00000266505.12 linkuse as main transcript	c.1055T>C	p.Leu352Pro	missense_variant	10/15	1	NM_033123.4	ENSP00000266505.7	Q86YW0-1
PLCZ1	ENST00000648272.1 linkuse as main transcript	c.1178T>C	p.Leu393Pro	missense_variant	9/14			ENSP00000497636.1	A0A3B3ISW9
PLCZ1	ENST00000539875.5 linkuse as main transcript	c.476T>C	p.Leu159Pro	missense_variant	6/11	1		ENSP00000445026.1	Q86YW0-2
PLCZ1	ENST00000318197.10 linkuse as main transcript	n.*920T>C		non_coding_transcript_exon_variant	10/15	1		ENSP00000326397.6	F5H474
PLCZ1	ENST00000318197.10 linkuse as main transcript	n.*920T>C		3_prime_UTR_variant	10/15	1		ENSP00000326397.6	F5H474

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000842

AC:

AN:

249428

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

134822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000610

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:

0.0000151

AC:

AN:

1459934

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000470

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.1055T>C (p.L352P) alteration is located in exon 10 (coding exon 9) of the PLCZ1 gene. This alteration results from a T to C substitution at nucleotide position 1055, causing the leucine (L) at amino acid position 352 to be replaced by a proline (P). 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

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

.;.;D;.;.;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.8

.;.;H;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.8

.;D;D;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

.;D;D;D;D;D

Sift4G

Uncertain

0.0030

.;D;D;D;.;.

Polyphen

1.0

.;D;D;.;.;.

Vest4

0.98, 0.99

MutPred

0.74

.;.;Gain of sheet (P = 0.0043);.;.;.;

MVP

0.94

MPC

0.16

ClinPred

0.96

GERP RS

5.9

Varity_R

0.86

gMVP

0.87

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