1-237882534-G-C

Variant names:

• chr1-237882534-G-C
• rs34478438
• NM_021186.5:c.1511C>G

Variant summary

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

The NM_021186.5(ZP4):​c.1511C>G​(p.Ser504Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S504L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZP4 NM_021186.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.646
• Publications: 6 publications found

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)

ENSG00000237250 (HGNC:):

ACMG classification

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
ZP4	NM_021186.5	c.1511C>G	p.Ser504Trp	missense_variant	Exon 12 of 12	ENST00000366570.5	NP_067009.1
LOC100130331	NR_027247.2	n.376G>C		non_coding_transcript_exon_variant	Exon 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP4	ENST00000366570.5	c.1511C>G	p.Ser504Trp	missense_variant	Exon 12 of 12	1	NM_021186.5	ENSP00000355529.4
ENSG00000237250	ENST00000450451.1	n.376G>C		non_coding_transcript_exon_variant	Exon 4 of 12	1
ZP4	ENST00000611898.4	c.1511C>G	p.Ser504Trp	missense_variant	Exon 12 of 13	5		ENSP00000482304.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450860 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721708

African (AFR) AF: 0.00 AC: 0 AN: 32496

American (AMR) AF: 0.00 AC: 0 AN: 40496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 84932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108750

Other (OTH) AF: 0.0000167 AC: 1 AN: 59926

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.72	T;.
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		0.65
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	.;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.025	.;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;D
Vest4		0.55
MutPred		0.62		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.46
MPC		0.078
ClinPred		0.77	D
GERP RS		3.3
Varity_R		0.065
gMVP		0.50
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34478438; hg19: chr1-238045834;