1-237882756-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021186.5(ZP4):c.1481C>T(p.Pro494Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,614,084 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 64 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 69 hom. )

Consequence

ZP4
NM_021186.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.50

Publications

6 publications found

Variant links:

Genes affected

ZP4 (HGNC:15770): (zona pellucida glycoprotein 4) 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 nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a consensus furin cleavage site, and a C-terminal 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. Previously, this gene has been referred to as ZP1 or ZPB and thought to have similar functions as mouse Zp1. However, a human gene with higher similarity and chromosomal synteny to mouse Zp1 has been assigned the symbol ZP1 and this gene has been assigned the symbol ZP4. [provided by RefSeq, Jul 2008]

ZP4 Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ZP4 links:

ENSG00000237250 (HGNC:):

ENSG00000237250 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002118498).

BP6

Variant 1-237882756-G-A is Benign according to our data. Variant chr1-237882756-G-A is described in ClinVar as [Benign]. Clinvar id is 773296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP4	NM_021186.5 link	c.1481C>T	p.Pro494Leu	missense_variant	Exon 11 of 12	ENST00000366570.5	NP_067009.1	Q12836
LOC100130331	NR_027247.2 link	n.410+188G>A		intron_variant	Intron 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZP4	ENST00000366570.5 link	c.1481C>T	p.Pro494Leu	missense_variant	Exon 11 of 12	1	NM_021186.5	ENSP00000355529.4	Q12836
ENSG00000237250	ENST00000450451.1 link	n.410+188G>A		intron_variant	Intron 4 of 11	1
ZP4	ENST00000611898.4 link	c.1481C>T	p.Pro494Leu	missense_variant	Exon 11 of 13	5		ENSP00000482304.1	Q12836

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2444

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0544

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00442

AC:

1112

AN:

251384

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.0543

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00194

AC:

2835

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

1248

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.0578

AC:

1935

AN:

33476

American (AMR)

AF:

0.00373

AC:

167

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.000162

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000296

AC:

329

AN:

1111980

Other (OTH)

AF:

0.00517

AC:

312

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

136

272

407

543

679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0161

AC:

2446

AN:

152264

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1136

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0543

AC:

2254

AN:

41536

American (AMR)

AF:

0.00824

AC:

126

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68018

Other (OTH)

AF:

0.0133

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

120

240

361

481

601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00642

Hom.:

Bravo

AF:

0.0181

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0527

AC:

232

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00529

AC:

642

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 06, 2018

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

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.62

T;.

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L

PhyloP100

2.5

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.8

.;D

REVEL

Benign

0.094

Sift

Benign

0.45

.;T

Sift4G

Benign

0.20

T;T

Polyphen

0.030

B;B

Vest4

0.19

MVP

0.081

MPC

0.015

ClinPred

0.014

GERP RS

3.3

Varity_R

0.033

gMVP

0.37

Mutation Taster

=92/8

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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1-237882756-G-A

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