dbSNP rs61696422: ZPBP:p.Arg25Pro (chr7-50093121-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_007009.3(ZPBP):c.74G>C(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,580,458 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0017 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 37 hom. )

Consequence

ZPBP
NM_007009.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.0650

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:

ENSG00000287521 (HGNC:):

ENSG00000287521 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025164187).

BP6

Variant 7-50093121-C-G is Benign according to our data. Variant chr7-50093121-C-G is described in ClinVar as [Benign]. Clinvar id is 3044430.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00166 (253/152264) while in subpopulation EAS AF= 0.0468 (242/5168). AF 95% confidence interval is 0.042. There are 6 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZPBP	NM_007009.3 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 8	ENST00000046087.7	NP_008940.2	Q9BS86-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZPBP	ENST00000046087.7 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 8	1	NM_007009.3	ENSP00000046087.2		Q9BS86-1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

255

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0473

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00333

AC:

610

AN:

183006

Hom.:

AF XY:

0.00330

AC XY:

330

AN XY:

100112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000707

Gnomad ASJ exome

AF:

0.000226

Gnomad EAS exome

AF:

0.0427

Gnomad SAS exome

AF:

0.000238

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000260

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.00137

AC:

1957

AN:

1428194

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

958

AN XY:

707642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000495

Gnomad4 ASJ exome

AF:

0.000392

Gnomad4 EAS exome

AF:

0.0474

Gnomad4 SAS exome

AF:

0.000512

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000137

Gnomad4 OTH exome

AF:

0.00153

GnomAD4 genome

AF:

0.00166

AC:

253

AN:

152264

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0468

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00196

ExAC

AF:

0.00233

AC:

274

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ZPBP-related disorder

Benign:1

Aug 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.9

DANN

Benign

0.58

DEOGEN2

Benign

0.095

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.067

Sift

Benign

0.28

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;.

Vest4

0.26

MVP

0.30

MPC

0.25

ClinPred

0.029

GERP RS

-3.3

Varity_R

0.13

gMVP

0.51

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

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