7-76425078-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000336517.8(ZP3):c.-40C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,428 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 25 hom. )

Consequence

ZP3
ENST00000336517.8 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -6.37

Publications

1 publications found

Variant links:

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

ZP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 7-76425078-C-T is Benign according to our data. Variant chr7-76425078-C-T is described in CliVar as Benign. Clinvar id is 713157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76425078-C-T is described in CliVar as Benign. Clinvar id is 713157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76425078-C-T is described in CliVar as Benign. Clinvar id is 713157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76425078-C-T is described in CliVar as Benign. Clinvar id is 713157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP3	NM_001110354.2 link	c.114C>T	p.Ser38Ser	synonymous_variant	Exon 1 of 8	ENST00000394857.8	NP_001103824.1	P21754-1
ZP3	NM_007155.6 link	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9		NP_009086.4	P21754-3
ZP3	NM_007155.6 link	c.-40C>T		5_prime_UTR_variant	Exon 2 of 9		NP_009086.4	P21754-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZP3	ENST00000336517.8 link	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	1		ENSP00000337310.4	P21754-3
ZP3	ENST00000394857.8 link	c.114C>T	p.Ser38Ser	synonymous_variant	Exon 1 of 8	1	NM_001110354.2	ENSP00000378326.3	P21754-1
ZP3	ENST00000336517.8 link	c.-40C>T		5_prime_UTR_variant	Exon 2 of 9	1		ENSP00000337310.4	P21754-3

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

305

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00747

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00227

AC:

567

AN:

249546

AF XY:

0.00252

show subpopulations

Gnomad AFR exome

AF:

0.000872

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.00261

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00340

AC:

4974

AN:

1461206

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

2492

AN XY:

726870

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.000493

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00637

AC:

549

AN:

86178

European-Finnish (FIN)

AF:

0.000264

AC:

AN:

53058

Middle Eastern (MID)

AF:

0.00815

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00364

AC:

4042

AN:

1111872

Other (OTH)

AF:

0.00391

AC:

236

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

297

594

892

1189

1486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00199

AC:

303

AN:

152222

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

41534

American (AMR)

AF:

0.000982

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00706

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00335

AC:

228

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00264

Hom.:

Bravo

AF:

0.00183

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00491

EpiControl

AF:

0.00297

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZP3: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.20

(source)

DANN

Benign

0.37

PhyloP100

-6.4

PromoterAI

-0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over