7-50018323-A-G

Variant names:

• chr7-50018323-A-G
• rs139249676
• NM_007009.3:c.707-7T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_007009.3(ZPBP):​c.707-7T>C variant causes a splice region, 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (10 hom.)
• Consequence: ZPBP NM_007009.3 splice_region, intron
• Scores: Splicing: ADA: 0.001836
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.34
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -11 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 no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZPBP	NM_007009.3	c.707-7T>C		splice_region_variant, intron_variant	Intron 5 of 7	ENST00000046087.7	NP_008940.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZPBP	ENST00000046087.7	c.707-7T>C		splice_region_variant, intron_variant	Intron 5 of 7	1	NM_007009.3	ENSP00000046087.2
ZPBP	ENST00000419417.5	c.704-7T>C		splice_region_variant, intron_variant	Intron 5 of 7	1		ENSP00000402071.1
ZPBP	ENST00000491129.5	n.241-34804T>C		intron_variant	Intron 1 of 3	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

GnomAD2 exomes AF: 0.00135 AC: 335 AN: 248572 AF XY: 0.00111

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 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

African (AFR) AF: 0.0180 AC: 589 AN: 32740

American (AMR) AF: 0.00103 AC: 46 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52516

Middle Eastern (MID) AF: 0.00354 AC: 15 AN: 4240

European-Non Finnish (NFE) AF: 0.0000422 AC: 46 AN: 1089954

Other (OTH) AF: 0.00121 AC: 72 AN: 59276

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

African (AFR) AF: 0.0167 AC: 695 AN: 41556

American (AMR) AF: 0.00197 AC: 30 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67920

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

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: no assertion criteria provided

Submissions by phenotype

ZPBP-related disorder Benign:1

Mar 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs139249676; hg19: chr7-50057919;