12-18695010-C-T

Variant names:

• chr12-18695010-C-T
• rs1360900704
• NM_033123.4:c.1361G>A

Variant summary

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

The NM_033123.4(PLCZ1):​c.1361G>A​(p.Gly454Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

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]

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=0.39731655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCZ1	NM_033123.4	c.1361G>A	p.Gly454Asp	missense_variant	Exon 12 of 15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1361G>A	p.Gly454Asp	missense_variant	Exon 12 of 15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1484G>A	p.Gly495Asp	missense_variant	Exon 11 of 14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.782G>A	p.Gly261Asp	missense_variant	Exon 8 of 11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*1226G>A		non_coding_transcript_exon_variant	Exon 12 of 15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*1226G>A		3_prime_UTR_variant	Exon 12 of 15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250884 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135604

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459882 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726338

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1361G>A (p.G454D) alteration is located in exon 12 (coding exon 11) of the PLCZ1 gene. This alteration results from a G to A substitution at nucleotide position 1361, causing the glycine (G) at amino acid position 454 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	Benign	0.20
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;D;.;.
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.82	T;T;D;T;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	.;.;M;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.1	.;D;D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.059	.;T;T;D;T
Sift4G	Uncertain	0.021	.;D;T;T;.
Polyphen		0.99, 0.99	.;D;D;.;.
Vest4		0.49, 0.53, 0.50
MVP		0.68
MPC		0.14
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.23
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1360900704; hg19: chr12-18847944;