NM_033123.4:c.1361G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39731655).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCZ1	NM_033123.4	MANE Select	c.1361G>A	p.Gly454Asp	missense	Exon 12 of 15	NP_149114.2
	PLCZ1	NM_001330774.2		c.1049G>A	p.Gly350Asp	missense	Exon 12 of 15	NP_001317703.1	Q86YW0-3
	PLCZ1	NM_001330769.1		c.782G>A	p.Gly261Asp	missense	Exon 8 of 11	NP_001317698.1	Q86YW0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCZ1	ENST00000266505.12	TSL:1 MANE Select	c.1361G>A	p.Gly454Asp	missense	Exon 12 of 15	ENSP00000266505.7	Q86YW0-1
	PLCZ1	ENST00000648272.1		c.1484G>A	p.Gly495Asp	missense	Exon 11 of 14	ENSP00000497636.1	A0A3B3ISW9
	PLCZ1	ENST00000539875.5	TSL:1	c.782G>A	p.Gly261Asp	missense	Exon 8 of 11	ENSP00000445026.1	Q86YW0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250884 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110432

Other (OTH) AF: 0.0000166 AC: 1 AN: 60314

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.41
Sift	Benign	0.059	T
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.49
MVP		0.68
MPC		0.14
ClinPred		0.97	D
GERP RS		4.0
PromoterAI		0.017	Neutral
Varity_R		0.23
gMVP		0.62
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs1360900704; hg19: chr12-18847944;