12-18688215-T-A

Variant names:

• chr12-18688215-T-A
• rs757326350
• NM_033123.4:c.1465A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3 PP5_Moderate

The NM_033123.4(PLCZ1):​c.1465A>T​(p.Ile489Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004120402: This variant was reported in the homozygous state in patients with male infertility with functional studies showing this variant is deleterious, leading to the absence of the protein in sperm (Escoffier et al 2016. PubMed ID: 26721930).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.50
• Publications: 18 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004120402: This variant was reported in the homozygous state in patients with male infertility with functional studies showing this variant is deleterious, leading to the absence of the protein in sperm (Escoffier et al 2016. PubMed ID: 26721930).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 12-18688215-T-A is Pathogenic according to our data. Variant chr12-18688215-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 271283.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1465A>T	p.Ile489Phe	missense	Exon 13 of 15	NP_149114.2
	PLCZ1	NM_001330774.2		c.1153A>T	p.Ile385Phe	missense	Exon 13 of 15	NP_001317703.1	Q86YW0-3
	PLCZ1	NM_001330769.1		c.886A>T	p.Ile296Phe	missense	Exon 9 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.1465A>T	p.Ile489Phe	missense	Exon 13 of 15	ENSP00000266505.7	Q86YW0-1
	PLCZ1	ENST00000648272.1		c.1588A>T	p.Ile530Phe	missense	Exon 12 of 14	ENSP00000497636.1	A0A3B3ISW9
	PLCZ1	ENST00000539875.5	TSL:1	c.886A>T	p.Ile296Phe	missense	Exon 9 of 11	ENSP00000445026.1	Q86YW0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248072 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00000206 AC: 3 AN: 1455114 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724212

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.0000449 AC: 2 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108838

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	PLCZ1-related disorder (1)
1	-	-	Spermatogenic failure 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.61		Gain of catalytic residue at L484 (P = 0.0134)
MVP		0.83
MPC		0.079
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.70
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs757326350; hg19: chr12-18841149;