rs2005354

Positions:

• chr7-76437443-T-C
• chr7-76437443-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZP3	NM_001110354.2	c.832-2807T>C		intron_variant		ENST00000394857.8
ZP3	NM_007155.6	c.679-2807T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZP3	ENST00000394857.8	c.832-2807T>C		intron_variant		1	NM_001110354.2	P1

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

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.0431

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.231

Alfa AF: 0.106 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.5
DANN	Benign	0.48

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: rs2005354; hg19: chr7-76066760;