1-237885415-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021186.5(ZP4):​c.1136C>G​(p.Pro379Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZP4
NM_021186.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.368

Publications

0 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZP4NM_021186.5 linkc.1136C>G p.Pro379Arg missense_variant Exon 8 of 12 ENST00000366570.5 NP_067009.1 Q12836
LOC100130331NR_027247.2 linkn.410+2847G>C intron_variant Intron 4 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZP4ENST00000366570.5 linkc.1136C>G p.Pro379Arg missense_variant Exon 8 of 12 1 NM_021186.5 ENSP00000355529.4 Q12836
ENSG00000237250ENST00000450451.1 linkn.410+2847G>C intron_variant Intron 4 of 11 1
ZP4ENST00000611898.4 linkc.1136C>G p.Pro379Arg missense_variant Exon 8 of 13 5 ENSP00000482304.1 Q12836

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000802
AC:
2
AN:
249322
AF XY:
0.00000742
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460182
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726292
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33412
American (AMR)
AF:
0.00
AC:
0
AN:
44524
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25906
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86074
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53360
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
0.00000630
AC:
7
AN:
1111208
Other (OTH)
AF:
0.00
AC:
0
AN:
60268
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74336
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41424
American (AMR)
AF:
0.0000655
AC:
1
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5172
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 03, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1136C>G (p.P379R) alteration is located in exon 8 (coding exon 8) of the ZP4 gene. This alteration results from a C to G substitution at nucleotide position 1136, causing the proline (P) at amino acid position 379 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.055
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
15
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;D
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.75
T;.
M_CAP
Benign
0.019
T
MetaRNN
Uncertain
0.58
D;D
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Uncertain
2.8
M;M
PhyloP100
0.37
PrimateAI
Benign
0.36
T
PROVEAN
Pathogenic
-7.0
.;D
REVEL
Uncertain
0.37
Sift
Benign
0.039
.;D
Sift4G
Benign
0.077
T;T
Polyphen
0.59
P;P
Vest4
0.27
MutPred
0.83
Gain of catalytic residue at P379 (P = 0.0791);Gain of catalytic residue at P379 (P = 0.0791);
MVP
0.62
MPC
0.027
ClinPred
0.84
D
GERP RS
1.6
Varity_R
0.43
gMVP
0.53
Mutation Taster
=93/7
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs757781486; hg19: chr1-238048715; API