7-76437443-T-C

Variant names:

• chr7-76437443-T-C
• rs2005354
• NM_001110354.2:c.832-2807T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001110354.2(ZP3):​c.832-2807T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 144,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (0 hom., cov: 36)
• Consequence: ZP3 NM_001110354.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.166
• Publications: 2 publications found

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]

ZP3 Gene-Disease associations (from GenCC):

• oocyte maturation defect 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• female infertility due to zona pellucida defect

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• inherited oocyte maturation defect

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110354.2. 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
	ZP3	NM_001110354.2	MANE Select	c.832-2807T>C		intron	N/A	NP_001103824.1
	ZP3	NM_007155.6		c.679-2807T>C		intron	N/A	NP_009086.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZP3	ENST00000394857.8	TSL:1 MANE Select	c.832-2807T>C		intron	N/A	ENSP00000378326.3
	ZP3	ENST00000336517.8	TSL:1	c.679-2807T>C		intron	N/A	ENSP00000337310.4
	ZP3	ENST00000394860.3	TSL:2	c.295-2807T>C		intron	N/A	ENSP00000378329.3

Frequencies

GnomAD3 genomes AF: 0.201 AC: 29087 AN: 144602 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.232

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.201 AC: 29086 AN: 144712 Hom.: 0 Cov.: 36 AF XY: 0.196 AC XY: 13889 AN XY: 70698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.141 AC: 5605 AN: 39638

American (AMR) AF: 0.178 AC: 2584 AN: 14504

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 813 AN: 3252

East Asian (EAS) AF: 0.0431 AC: 220 AN: 5104

South Asian (SAS) AF: 0.182 AC: 823 AN: 4516

European-Finnish (FIN) AF: 0.169 AC: 1698 AN: 10018

Middle Eastern (MID) AF: 0.321 AC: 86 AN: 268

European-Non Finnish (NFE) AF: 0.256 AC: 16517 AN: 64550

Other (OTH) AF: 0.231 AC: 463 AN: 2006

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.106 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.5
DANN	Benign	0.48
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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: rs2005354; hg19: chr7-76066760;