17-39871618-G-C

Position:

• chr17-39871618-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199321.3(ZPBP2):​c.399G>C​(p.Met133Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZPBP2 NM_199321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.143044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZPBP2	NM_199321.3	c.399G>C	p.Met133Ile	missense_variant	4/8	ENST00000348931.9	NP_955353.1
ZPBP2	NM_198844.3	c.333G>C	p.Met111Ile	missense_variant	3/7		NP_942141.2
ZPBP2	XM_047435318.1	c.399G>C	p.Met133Ile	missense_variant	4/7		XP_047291274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZPBP2	ENST00000348931.9	c.399G>C	p.Met133Ile	missense_variant	4/8	1	NM_199321.3	ENSP00000335384	P1
ZPBP2	ENST00000377940.3	c.333G>C	p.Met111Ile	missense_variant	3/7	1		ENSP00000367174
ZPBP2	ENST00000584588.5	c.399G>C	p.Met133Ile	missense_variant	4/7	5		ENSP00000462067
ZPBP2	ENST00000583811.5	c.53-652G>C		intron_variant		3		ENSP00000462463

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.399G>C (p.M133I) alteration is located in exon 4 (coding exon 4) of the ZPBP2 gene. This alteration results from a G to C substitution at nucleotide position 399, causing the methionine (M) at amino acid position 133 to be replaced by an isoleucine (I). 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	0.33
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.039	T;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	0.76	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.75	N;.;N
REVEL	Benign	0.041
Sift	Benign	0.45	T;.;T
Sift4G	Uncertain	0.041	D;D;D
Polyphen		0.15	B;.;B
Vest4		0.20
MutPred		0.43		Gain of methylation at K128 (P = 0.083);Gain of methylation at K128 (P = 0.083);.;
MVP		0.061
MPC		0.16
ClinPred		0.44	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38027871;