chr12-18696167-T-C

Position:

• chr12-18696167-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_033123.4(PLCZ1):​c.1274A>G​(p.Asn425Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,403,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.11

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-18696167-T-C is Pathogenic according to our data. Variant chr12-18696167-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2578005.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.1274A>G	p.Asn425Ser	missense_variant	11/15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1274A>G	p.Asn425Ser	missense_variant	11/15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1397A>G	p.Asn466Ser	missense_variant	10/14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.695A>G	p.Asn232Ser	missense_variant	7/11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*1139A>G		non_coding_transcript_exon_variant	11/15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*1139A>G		3_prime_UTR_variant	11/15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403534 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 700580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Bravo AF: 0.0000189

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

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	.;D;D;D;D
REVEL	Uncertain	0.55
Sift	Benign	0.048	.;D;D;D;T
Sift4G	Benign	0.077	.;T;D;T;.
Polyphen		1.0	.;D;D;.;.
Vest4		0.72, 0.74, 0.72
MutPred		0.62		.;.;Gain of catalytic residue at I426 (P = 0);.;.;
MVP		0.80
MPC		0.14
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1310560334; hg19: chr12-18849101;