1-237882520-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021186.5(ZP4):​c.1525G>A​(p.Val509Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,453,656 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: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ZP4
NM_021186.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0110

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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12247315).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZP4NM_021186.5 linkc.1525G>A p.Val509Met missense_variant Exon 12 of 12 ENST00000366570.5 NP_067009.1 Q12836
LOC100130331NR_027247.2 linkn.362C>T non_coding_transcript_exon_variant Exon 4 of 12

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZP4ENST00000366570.5 linkc.1525G>A p.Val509Met missense_variant Exon 12 of 12 1 NM_021186.5 ENSP00000355529.4 Q12836
ENSG00000237250ENST00000450451.1 linkn.362C>T non_coding_transcript_exon_variant Exon 4 of 12 1
ZP4ENST00000611898.4 linkc.1525G>A p.Val509Met missense_variant Exon 12 of 13 5 ENSP00000482304.1 Q12836

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000823
AC:
2
AN:
243078
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000643
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000124
AC:
18
AN:
1453656
Hom.:
0
Cov.:
31
AF XY:
0.00000968
AC XY:
7
AN XY:
723220
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32722
American (AMR)
AF:
0.0000482
AC:
2
AN:
41498
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25784
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39632
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53316
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5738
European-Non Finnish (NFE)
AF:
0.0000144
AC:
16
AN:
1109650
Other (OTH)
AF:
0.00
AC:
0
AN:
60074
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
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

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
Cov.:
32
Alfa
AF:
0.0000413
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 08, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1525G>A (p.V509M) alteration is located in exon 12 (coding exon 12) of the ZP4 gene. This alteration results from a G to A substitution at nucleotide position 1525, causing the valine (V) at amino acid position 509 to be replaced by a methionine (M). 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
0.12
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
10
DANN
Benign
0.95
DEOGEN2
Benign
0.045
T;T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.75
T;.
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.3
L;L
PhyloP100
-0.011
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.66
.;N
REVEL
Benign
0.081
Sift
Benign
0.17
.;T
Sift4G
Benign
0.56
T;T
Polyphen
0.18
B;B
Vest4
0.22
MutPred
0.32
Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP
0.41
MPC
0.016
ClinPred
0.062
T
GERP RS
2.4
Varity_R
0.031
gMVP
0.40
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs911377229; hg19: chr1-238045820; API