7-50081820-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007009.3(ZPBP):c.288A>G(p.Ile96Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ZPBP NM_007009.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.572

Genes affected

ZPBP (HGNC:15662): (zona pellucida binding protein) ZPBP is one of several proteins that are thought to participate in secondary binding between acrosome-reacted sperm and the egg-specific extracellular matrix, the zona pellucida (McLeskey et al., 1998 [PubMed 9378618]).[supplied by OMIM, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPBP	NM_007009.3	c.288A>G	p.Ile96Met	missense_variant	3/8	ENST00000046087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPBP	ENST00000046087.7	c.288A>G	p.Ile96Met	missense_variant	3/8	1	NM_007009.3	P4
ZPBP	ENST00000419417.5	c.288A>G	p.Ile96Met	missense_variant	3/8	1		A2
ZPBP	ENST00000450231.1	c.171A>G	p.Ile57Met	missense_variant	5/5	3
ZPBP	ENST00000413331.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 33

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 Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.288A>G (p.I96M) alteration is located in exon 3 (coding exon 3) of the ZPBP gene. This alteration results from a A to G substitution at nucleotide position 288, causing the isoleucine (I) at amino acid position 96 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	0.22
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	0.84	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.99	D;.;.
Vest4		0.48
MutPred		0.78		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.59
MPC		0.68
ClinPred		0.93	D
GERP RS		2.5
Varity_R		0.30
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1463701246; hg19: chr7-50121416;