rs1554625334

Variant names:

• chr7-76429602-G-A
• rs1554625334
• NM_001110354.2:c.400G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001110354.2(ZP3):​c.400G>A​(p.Ala134Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,830 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZP3 NM_001110354.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.74

Genes affected

ZP3 (HGNC:13189): (zona pellucida glycoprotein 3) The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by this gene is a structural component of the zona pellucida and functions in primary binding and induction of the sperm acrosome reaction. The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a C-terminal consensus furin cleavage site, and a transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies. A variation in the last exon of this gene has previously served as the basis for an additional ZP3 locus; however, sequence and literature review reveals that there is only one full-length ZP3 locus in the human genome. Another locus encoding a bipartite transcript designated POMZP3 contains a duplication of the last four exons of ZP3, including the above described variation, and maps closely to this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 7-76429602-G-A is Pathogenic according to our data. Variant chr7-76429602-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 437933.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-76429602-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP3	NM_001110354.2	c.400G>A	p.Ala134Thr	missense_variant	Exon 2 of 8	ENST00000394857.8	NP_001103824.1
ZP3	NM_007155.6	c.247G>A	p.Ala83Thr	missense_variant	Exon 3 of 9		NP_009086.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP3	ENST00000394857.8	c.400G>A	p.Ala134Thr	missense_variant	Exon 2 of 8	1	NM_001110354.2	ENSP00000378326.3
ZP3	ENST00000336517.8	c.247G>A	p.Ala83Thr	missense_variant	Exon 3 of 9	1		ENSP00000337310.4
ZP3	ENST00000416245	c.-129G>A		5_prime_UTR_variant	Exon 1 of 7	2		ENSP00000411955.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Empty follicle syndrome Pathogenic:1

-

Zi-Jiang Chen Lab, Shandong University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: phenotyping only;research

We identified a heterozygous missense mutation of ZP3 c.400 G>A (NM_001110354.1) from a large family with multiple women affected by empty follicle syndrome (EFS). This mutation was also found in another big family affected by EFS as well as in two additional simplex cases with the same phenotype (the mutation of one of the simplex cases was de novo). The mutation was absent in public databases including dbSNP, 1000 Genomes Project, the NHLBI Exome Variant Server (EVS), the Exome Aggregation Consortium (ExAC) and gnomAD datebase. The mutation was also absent in our in-house 2,213 population-based Han Chinese controls and 400 healthy Han Chinese women with normal fertility. -

Oocyte maturation defect 3 Pathogenic:1

Apr 10, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.9	.;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.54
Sift	Benign	0.042	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		1.0	D;D
Vest4		0.54
MutPred		0.82		.;Loss of phosphorylation at T131 (P = 0.2232);
MVP		0.77
MPC		0.068
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.81

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: rs1554625334; hg19: chr7-76058919; COSMIC: COSV60630294; COSMIC: COSV60630294;