rs61696422

chr7-50093121-C-Gchr7-50093121-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: ZPBP NM_007009.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0650

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]

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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 GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPBP	NM_007009.3	c.74G>C	p.Arg25Pro	missense_variant	1/8	ENST00000046087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPBP	ENST00000046087.7	c.74G>C	p.Arg25Pro	missense_variant	1/8	1	NM_007009.3	P4
ZPBP	ENST00000419417.5	c.74G>C	p.Arg25Pro	missense_variant	1/8	1		A2
ZPBP	ENST00000450231.1	c.11-3412G>C		intron_variant		3
ZPBP	ENST00000413331.1	c.74G>C	p.Arg25Pro	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152148 Hom.: 6 Cov.: 32

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.: 9 AF XY: 0.00330 AC XY: 330 AN XY: 100112

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.: 37 Cov.: 30 AF XY: 0.00135 AC XY: 958 AN XY: 707642

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.: 6 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74470

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.: 4

Bravo AF: 0.00196

ExAC AF: 0.00233 AC: 274

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZPBP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2019

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	T
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	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.58	T
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	T
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

Other links and lift over

dbSNP: rs61696422; hg19: chr7-50132717;