1-237885557-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021186.5(ZP4):​c.994G>A​(p.Gly332Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

ZP4
NM_021186.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.407

Publications

5 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: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.041502774).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZP4NM_021186.5 linkc.994G>A p.Gly332Ser missense_variant Exon 8 of 12 ENST00000366570.5 NP_067009.1 Q12836
LOC100130331NR_027247.2 linkn.410+2989C>T intron_variant Intron 4 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZP4ENST00000366570.5 linkc.994G>A p.Gly332Ser missense_variant Exon 8 of 12 1 NM_021186.5 ENSP00000355529.4 Q12836
ENSG00000237250ENST00000450451.1 linkn.410+2989C>T intron_variant Intron 4 of 11 1
ZP4ENST00000611898.4 linkc.994G>A p.Gly332Ser missense_variant Exon 8 of 13 5 ENSP00000482304.1 Q12836

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000176
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000160
AC:
4
AN:
250552
AF XY:
0.0000222
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000657
AC:
96
AN:
1461304
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
39
AN XY:
726934
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44582
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26058
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86142
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000854
AC:
95
AN:
1111826
Other (OTH)
AF:
0.00
AC:
0
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
6
12
19
25
31
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.0000789
AC:
12
AN:
152088
Hom.:
0
Cov.:
32
AF XY:
0.0000808
AC XY:
6
AN XY:
74292
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41394
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000176
AC:
12
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000160
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
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
Sep 20, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.994G>A (p.G332S) alteration is located in exon 8 (coding exon 8) of the ZP4 gene. This alteration results from a G to A substitution at nucleotide position 994, causing the glycine (G) at amino acid position 332 to be replaced by a serine (S). 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
0.064
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
4.2
DANN
Benign
0.61
DEOGEN2
Benign
0.10
T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.0048
N
LIST_S2
Benign
0.54
T;.
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.73
N;N
PhyloP100
-0.41
PrimateAI
Benign
0.24
T
PROVEAN
Benign
0.25
.;N
REVEL
Benign
0.044
Sift
Benign
0.79
.;T
Sift4G
Benign
0.82
T;T
Polyphen
0.27
B;B
Vest4
0.11
MVP
0.055
MPC
0.017
ClinPred
0.047
T
GERP RS
-4.4
Varity_R
0.075
gMVP
0.31
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs368326237; hg19: chr1-238048857; COSMIC: COSV63912103; API