1-237882534-G-A

Position:

• chr1-237882534-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021186.5(ZP4):​c.1511C>T​(p.Ser504Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,603,072 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (57 hom.)
• Consequence: ZP4 NM_021186.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.646

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]

ENSG00000237250 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003105253).
• BP6: Variant 1-237882534-G-A is Benign according to our data. Variant chr1-237882534-G-A is described in ClinVar as [Benign]. Clinvar id is 791844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0145 (2213/152218) while in subpopulation AFR AF= 0.0496 (2059/41536). AF 95% confidence interval is 0.0478. There are 52 homozygotes in gnomad4. There are 1071 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZP4	NM_021186.5	c.1511C>T	p.Ser504Leu	missense_variant	12/12	ENST00000366570.5	NP_067009.1
LOC100130331	NR_027247.2	n.376G>A		non_coding_transcript_exon_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZP4	ENST00000366570.5	c.1511C>T	p.Ser504Leu	missense_variant	12/12	1	NM_021186.5	ENSP00000355529.4
ENSG00000237250	ENST00000450451.1	n.376G>A		non_coding_transcript_exon_variant	4/12	1
ZP4	ENST00000611898.4	c.1511C>T	p.Ser504Leu	missense_variant	12/13	5		ENSP00000482304.1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2198 AN: 152100 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00363 AC: 873 AN: 240728 Hom.: 16 AF XY: 0.00260 AC XY: 339 AN XY: 130618

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000810

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00143 AC: 2073 AN: 1450854 Hom.: 57 Cov.: 31 AF XY: 0.00122 AC XY: 881 AN XY: 721704

Gnomad4 AFR exome AF: 0.0520

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000706

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000406

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.0145 AC: 2213 AN: 152218 Hom.: 52 Cov.: 32 AF XY: 0.0144 AC XY: 1071 AN XY: 74418

Gnomad4 AFR AF: 0.0496

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00201 Hom.: 8

Bravo AF: 0.0166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00439 AC: 533

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.2
DANN	Benign	0.72
DEOGEN2	Benign	0.060	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.60	T;.
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.16
Sift	Benign	0.27	.;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0030	B;B
Vest4		0.18
MVP		0.24
MPC		0.014
ClinPred		0.0063	T
GERP RS		3.3
Varity_R		0.036
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34478438; hg19: chr1-238045834;