chr12-18696161-C-T

Position:

chr12-18696161-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_033123.4(PLCZ1):c.1280G>A(p.Gly427Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000034 in 1,530,918 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000033 ( 1 hom. )

Consequence

PLCZ1
NM_033123.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.03

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 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, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCZ1	NM_033123.4 linkuse as main transcript	c.1280G>A	p.Gly427Asp	missense_variant	11/15	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.1280G>A	p.Gly427Asp	missense_variant	11/15	1	NM_033123.4	ENSP00000266505.7	Q86YW0-1
PLCZ1	ENST00000648272.1 linkuse as main transcript	c.1403G>A	p.Gly468Asp	missense_variant	10/14			ENSP00000497636.1	A0A3B3ISW9
PLCZ1	ENST00000539875.5 linkuse as main transcript	c.701G>A	p.Gly234Asp	missense_variant	7/11	1		ENSP00000445026.1	Q86YW0-2
PLCZ1	ENST00000318197.10 linkuse as main transcript	n.*1145G>A		non_coding_transcript_exon_variant	11/15	1		ENSP00000326397.6	F5H474
PLCZ1	ENST00000318197.10 linkuse as main transcript	n.*1145G>A		3_prime_UTR_variant	11/15	1		ENSP00000326397.6	F5H474

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151490

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000569

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000375

AC:

AN:

240316

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

129794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000680

Gnomad FIN exome

AF:

0.000282

Gnomad NFE exome

AF:

0.00000926

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1379428

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

690068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000167

Gnomad4 FIN exome

AF:

0.000492

Gnomad4 NFE exome

AF:

0.00000384

Gnomad4 OTH exome

AF:

0.0000348

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151490

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73956

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000569

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000495

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

Feb 11, 2022

The c.1280G>A (p.G427D) alteration is located in exon 11 (coding exon 10) of the PLCZ1 gene. This alteration results from a G to A substitution at nucleotide position 1280, causing the glycine (G) at amino acid position 427 to be replaced by an aspartic acid (D). 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

0.34

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;.;H;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.8

.;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0010

.;D;D;D;.

Polyphen

1.0

.;D;D;.;.

Vest4

0.89, 0.90, 0.89

MutPred

0.82

.;.;Gain of catalytic residue at W424 (P = 0);.;.;

MVP

0.96

MPC

0.15

ClinPred

0.98

GERP RS

5.6

Varity_R

0.92

gMVP

0.78

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