Variant chr17-39876727-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_199321.3(ZPBP2):c.935G>T(p.Cys312Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,666 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: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZPBP2
NM_199321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

ZPBP2 (HGNC:20678): (zona pellucida binding protein 2) Predicted to be involved in acrosome assembly and binding activity of sperm to zona pellucida. Predicted to act upstream of or within membrane lipid metabolic process and regulation of gene expression. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZPBP2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZPBP2	NM_199321.3 linkuse as main transcript	c.935G>T	p.Cys312Phe	missense_variant	8/8	ENST00000348931.9	NP_955353.1
ZPBP2	NM_198844.3 linkuse as main transcript	c.869G>T	p.Cys290Phe	missense_variant	7/7		NP_942141.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZPBP2	ENST00000348931.9 linkuse as main transcript	c.935G>T	p.Cys312Phe	missense_variant	8/8	1	NM_199321.3	ENSP00000335384	P1	Q6X784-1
ZPBP2	ENST00000377940.3 linkuse as main transcript	c.869G>T	p.Cys290Phe	missense_variant	7/7	1		ENSP00000367174		Q6X784-2
ZPBP2	ENST00000584588.5 linkuse as main transcript	c.716G>T	p.Cys239Phe	missense_variant	7/7	5		ENSP00000462067
ZPBP2	ENST00000583811.5 linkuse as main transcript	c.581G>T	p.Cys194Phe	missense_variant	5/5	3		ENSP00000462463

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727132

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.935G>T (p.C312F) alteration is located in exon 8 (coding exon 8) of the ZPBP2 gene. This alteration results from a G to T substitution at nucleotide position 935, causing the cysteine (C) at amino acid position 312 to be replaced by a phenylalanine (F). 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

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Benign

0.87

DEOGEN2

Benign

0.33

T;.;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.4

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.9

D;.;.;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.93

MutPred

0.90

Loss of disorder (P = 0.066);.;.;.;

MVP

0.89

MPC

0.79

ClinPred

0.95

GERP RS

6.0

Varity_R

0.94

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over