7-50018323-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_007009.3(ZPBP):c.707-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,586,124 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (10 hom.)
• Consequence: ZPBP NM_007009.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001836
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.34

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 7-50018323-A-G is Benign according to our data. Variant chr7-50018323-A-G is described in ClinVar as [Benign]. Clinvar id is 3043780.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00487 (741/152102) while in subpopulation AFR AF= 0.0167 (695/41556). AF 95% confidence interval is 0.0157. There are 4 homozygotes in gnomad4. There are 350 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZPBP	NM_007009.3	c.707-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000046087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZPBP	ENST00000046087.7	c.707-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007009.3	P4
ZPBP	ENST00000419417.5	c.704-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A2
ZPBP	ENST00000491129.5	n.241-34804T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00486 AC: 738 AN: 151984 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00135 AC: 335 AN: 248572 Hom.: 1 AF XY: 0.00111 AC XY: 149 AN XY: 134588

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000933

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000538 AC: 771 AN: 1434022 Hom.: 10 Cov.: 26 AF XY: 0.000502 AC XY: 359 AN XY: 715204

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000422

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00487 AC: 741 AN: 152102 Hom.: 4 Cov.: 32 AF XY: 0.00471 AC XY: 350 AN XY: 74356

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00158 Hom.: 3

Bravo AF: 0.00524

Asia WGS AF: 0.000869 AC: 3 AN: 3466

EpiCase AF: 0.0000547

EpiControl AF: 0.000178

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

Mar 12, 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
BayesDel_noAF	Benign	-0.31
Cadd	Benign	15
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.10		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: rs139249676; hg19: chr7-50057919;