rs760923145

Variant names:

• chr1-237885221-T-A
• rs760923145
• NM_021186.5:c.1255A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-237885221-T-A
• chr1-237885221-T-C

Variant summary

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

The NM_021186.5(ZP4):​c.1255A>T​(p.Ile419Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. I419V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: ZP4 NM_021186.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031330884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP4	NM_021186.5	c.1255A>T	p.Ile419Phe	missense_variant	Exon 9 of 12	ENST00000366570.5	NP_067009.1
LOC100130331	NR_027247.2	n.410+2653T>A		intron_variant	Intron 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP4	ENST00000366570.5	c.1255A>T	p.Ile419Phe	missense_variant	Exon 9 of 12	1	NM_021186.5	ENSP00000355529.4
ENSG00000237250	ENST00000450451.1	n.410+2653T>A		intron_variant	Intron 4 of 11	1
ZP4	ENST00000611898.4	c.1255A>T	p.Ile419Phe	missense_variant	Exon 9 of 13	5		ENSP00000482304.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251468 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461888 Hom.: 1 Cov.: 32 AF XY: 0.0000591 AC XY: 43 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00217 AC: 86 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

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: 0.00 AC: 0 AN: 68036

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.78	T;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		0.26
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.5	.;D
REVEL	Uncertain	0.33
Sift	Benign	0.12	.;T
Sift4G	Uncertain	0.056	T;T
Polyphen		0.091	B;B
Vest4		0.21
MutPred		0.75		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.28
MPC		0.024
ClinPred		0.072	T
GERP RS		1.4
Varity_R		0.28
gMVP		0.64
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs760923145; hg19: chr1-238048521;