chr1-237885415-G-A

Variant names:

• chr1-237885415-G-A
• rs757781486
• NM_021186.5:c.1136C>T

Variant summary

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

The NM_021186.5(ZP4):​c.1136C>T​(p.Pro379Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P379R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZP4 NM_021186.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 0 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.1136C>T	p.Pro379Leu	missense_variant	Exon 8 of 12	ENST00000366570.5	NP_067009.1
LOC100130331	NR_027247.2	n.410+2847G>A		intron_variant	Intron 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP4	ENST00000366570.5	c.1136C>T	p.Pro379Leu	missense_variant	Exon 8 of 12	1	NM_021186.5	ENSP00000355529.4
ENSG00000237250	ENST00000450451.1	n.410+2847G>A		intron_variant	Intron 4 of 11	1
ZP4	ENST00000611898.4	c.1136C>T	p.Pro379Leu	missense_variant	Exon 8 of 13	5		ENSP00000482304.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.086	N
LIST_S2	Uncertain	0.86	D;.
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		0.37
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-7.4	.;D
REVEL	Uncertain	0.39
Sift	Benign	0.092	.;T
Sift4G	Benign	0.13	T;T
Polyphen		0.38	B;B
Vest4		0.16
MutPred		0.78		Gain of catalytic residue at P379 (P = 0.0061);Gain of catalytic residue at P379 (P = 0.0061);
MVP		0.55
MPC		0.022
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.28
gMVP		0.49
Mutation Taster		=86/14	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

Other links and lift over

dbSNP: rs757781486; hg19: chr1-238048715;