chr12-18699920-A-G

Position:

• chr12-18699920-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_033123.4(PLCZ1):​c.1048T>C​(p.Ser350Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.36

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 12-18699920-A-G is Pathogenic according to our data. Variant chr12-18699920-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 978090.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCZ1	NM_033123.4	c.1048T>C	p.Ser350Pro	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.1048T>C	p.Ser350Pro	missense_variant	10/15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1171T>C	p.Ser391Pro	missense_variant	9/14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.469T>C	p.Ser157Pro	missense_variant	6/11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*913T>C		non_coding_transcript_exon_variant	10/15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*913T>C		3_prime_UTR_variant	10/15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 17 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;D;.;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	4.0	.;.;H;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	.;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Benign	0.064	.;T;D;D;.;.
Polyphen		1.0	.;D;D;.;.;.
Vest4		0.87, 0.94, 0.89
MutPred		0.77		.;.;Loss of stability (P = 0.0302);.;.;.;
MVP		0.90
MPC		0.15
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.92
gMVP		0.84

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: rs1955655663; hg19: chr12-18852854;