Genetic Variant ZPBP:p.Leu239Val (chr7-50018308-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_007009.3(ZPBP):c.715C>G(p.Leu239Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,603,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ZPBP
NM_007009.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0430

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30683458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZPBP	NM_007009.3 link	c.715C>G	p.Leu239Val	missense_variant	Exon 6 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.715C>G	p.Leu239Val	missense_variant	Exon 6 of 8	1	NM_007009.3	ENSP00000046087.2	Q9BS86-1
ZPBP	ENST00000419417.5 link	c.712C>G	p.Leu238Val	missense_variant	Exon 6 of 8	1		ENSP00000402071.1	Q9BS86-2
ZPBP	ENST00000491129.5 link	n.241-34789C>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1451828

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

722786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33204

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

39474

South Asian (SAS)

AF:

0.00

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4506

European-Non Finnish (NFE)

AF:

0.0000289

AC:

AN:

1105356

Other (OTH)

AF:

0.0000167

AC:

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151762

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41354

American (AMR)

AF:

0.0000658

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67898

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.715C>G (p.L239V) alteration is located in exon 6 (coding exon 6) of the ZPBP gene. This alteration results from a C to G substitution at nucleotide position 715, causing the leucine (L) at amino acid position 239 to be replaced by a valine (V). 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

0.093

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

L;.

PhyloP100

-0.043

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.22

Sift

Benign

0.34

T;T

Sift4G

Uncertain

0.050

T;T

Polyphen

0.90

P;.

Vest4

0.14

MutPred

0.71

Loss of stability (P = 0.076);.;

MVP

0.53

MPC

0.41

ClinPred

0.70

GERP RS

-2.9

Varity_R

0.063

gMVP

0.23

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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7-50018308-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