12-18699896-C-G

Position:

• chr12-18699896-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033123.4(PLCZ1):​c.1072G>C​(p.Ala358Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0290

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: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]

PLCZ1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34388602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCZ1	NM_033123.4	c.1072G>C	p.Ala358Pro	missense_variant	10/15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1072G>C	p.Ala358Pro	missense_variant	10/15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1195G>C	p.Ala399Pro	missense_variant	9/14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.493G>C	p.Ala165Pro	missense_variant	6/11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*937G>C		non_coding_transcript_exon_variant	10/15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*937G>C		3_prime_UTR_variant	10/15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460460 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726542

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Sep 27, 2021

The c.1072G>C (p.A358P) alteration is located in exon 10 (coding exon 9) of the PLCZ1 gene. This alteration results from a G to C substitution at nucleotide position 1072, causing the alanine (A) at amino acid position 358 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	0.79
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;.;T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.65	T;T;T;T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.72	.;.;N;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.6	.;D;D;D;N;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	.;D;D;D;D;D
Sift4G	Uncertain	0.029	.;D;D;T;.;.
Polyphen		0.97, 0.98	.;D;D;.;.;.
Vest4		0.58, 0.50, 0.55
MutPred		0.61		.;.;Gain of sheet (P = 0.0221);.;.;.;
MVP		0.63
MPC		0.13
ClinPred		0.93	D
GERP RS		-1.2
Varity_R		0.48
gMVP		0.68

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: chr12-18852830;