Variant chr7-50031241-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007009.3(ZPBP):c.557A>G(p.Tyr186Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZPBP
NM_007009.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

Variant links:

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]

ZPBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPBP	NM_007009.3 linkuse as main transcript	c.557A>G	p.Tyr186Cys	missense_variant	5/8	ENST00000046087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPBP	ENST00000046087.7 linkuse as main transcript	c.557A>G	p.Tyr186Cys	missense_variant	5/8	1	NM_007009.3	P4	Q9BS86-1
ZPBP	ENST00000419417.5 linkuse as main transcript	c.554A>G	p.Tyr185Cys	missense_variant	5/8	1		A2	Q9BS86-2
ZPBP	ENST00000491129.5 linkuse as main transcript	n.240+24944A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250208

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460502

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spermatogenic failure 66

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

A heterozygous missense variation in exon 5 of the ZPBP gene that results in the amino acid substitution of cystine for tyrosine at codon 186 was detected. The variant was not observed in 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen2, MutationTaster, SIFT, REVEL and CADD. The variant validated by sanger sequencing showed a heterozygous status in mother, whereas paternal sample was not avaliable. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.77

Loss of catalytic residue at I185 (P = 0.0501);.;

MVP

0.83

MPC

0.79

ClinPred

0.98

GERP RS

5.3

Varity_R

0.28

gMVP

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over