chr7-76417007-A-G

Variant names:

• chr7-76417007-A-G
• rs1019096
• ENST00000336517.8:c.-66-8045A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000336517.8(ZP3):​c.-66-8045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 145,392 control chromosomes in the GnomAD database, including 26,559 homozygotes. 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 0.59 (26559 hom., cov: 24)
• Consequence: ZP3 ENST00000336517.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.765
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP3	NM_007155.6	c.-66-8045A>G		intron_variant	Intron 1 of 8		NP_009086.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP3	ENST00000336517.8	c.-66-8045A>G		intron_variant	Intron 1 of 8	1		ENSP00000337310.4

Frequencies

GnomAD3 genomes AF: 0.592 AC: 86045 AN: 145366 Hom.: 26533 Cov.: 24

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.583

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

GnomAD4 genome AF: 0.592 AC: 86082 AN: 145392 Hom.: 26559 Cov.: 24 AF XY: 0.586 AC XY: 41395 AN XY: 70600

African (AFR) AF: 0.751 AC: 29523 AN: 39332

American (AMR) AF: 0.549 AC: 7867 AN: 14322

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2225 AN: 3432

East Asian (EAS) AF: 0.556 AC: 2774 AN: 4992

South Asian (SAS) AF: 0.630 AC: 2920 AN: 4636

European-Finnish (FIN) AF: 0.418 AC: 3673 AN: 8782

Middle Eastern (MID) AF: 0.650 AC: 182 AN: 280

European-Non Finnish (NFE) AF: 0.529 AC: 35310 AN: 66716

Other (OTH) AF: 0.586 AC: 1176 AN: 2006

Alfa AF: 0.556 Hom.: 32396

Bravo AF: 0.609

Asia WGS AF: 0.529 AC: 1689 AN: 3200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.43
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1019096; hg19: chr7-76046324;