Genetic Variant ZPBP:p.Thr174Arg (chr7-50031277-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_007009.3(ZPBP):c.521C>G(p.Thr174Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00168 in 1,611,372 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 12 hom. )

Consequence

ZPBP
NM_007009.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.12

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

spermatogenic failure 66
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ZPBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014819652).

BP6

Variant 7-50031277-G-C is Benign according to our data. Variant chr7-50031277-G-C is described in ClinVar as [Benign]. Clinvar id is 3034355.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 3 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZPBP	NM_007009.3 link	c.521C>G	p.Thr174Arg	missense_variant	Exon 5 of 8	ENST00000046087.7	NP_008940.2	Q9BS86-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZPBP	ENST00000046087.7 link	c.521C>G	p.Thr174Arg	missense_variant	Exon 5 of 8	1	NM_007009.3	ENSP00000046087.2	Q9BS86-1
ZPBP	ENST00000419417.5 link	c.518C>G	p.Thr173Arg	missense_variant	Exon 5 of 8	1		ENSP00000402071.1	Q9BS86-2
ZPBP	ENST00000491129.5 link	n.240+24908C>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

384

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00262

AC:

652

AN:

248842

AF XY:

0.00257

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00160

AC:

2329

AN:

1459112

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1119

AN XY:

725780

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33386

American (AMR)

AF:

0.000291

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.000547

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.0206

AC:

1096

AN:

53316

Middle Eastern (MID)

AF:

0.000231

AC:

AN:

4332

European-Non Finnish (NFE)

AF:

0.000983

AC:

1093

AN:

1111626

Other (OTH)

AF:

0.00125

AC:

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00252

AC:

383

AN:

152260

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

246

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41552

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0220

AC:

233

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00206

AC:

140

AN:

68012

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.000710

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00213

AC:

258

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ZPBP-related disorder

Benign:1

Oct 28, 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

0.22

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

4.1

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.81

MVP

0.90

MPC

0.75

ClinPred

0.089

GERP RS

5.3

Varity_R

0.59

gMVP

0.79

Mutation Taster

=94/6

polymorphism

(source)

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

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7-50031277-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over