7-50058101-A-G

Variant names:

• chr7-50058101-A-G
• rs76027725
• NM_007009.3:c.375T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_007009.3(ZPBP):​c.375T>C​(p.Leu125Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,613,794 control chromosomes in the GnomAD database, including 1,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.031 (89 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1125 hom.)
• Consequence: ZPBP NM_007009.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.268
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-50058101-A-G is Benign according to our data. Variant chr7-50058101-A-G is described in ClinVar as Benign. ClinVar VariationId is 3037675.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.031 (4727/152316) while in subpopulation NFE AF = 0.045 (3060/68028). AF 95% confidence interval is 0.0437. There are 89 homozygotes in GnomAd4. There are 2212 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 89 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007009.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZPBP	NM_007009.3	MANE Select	c.375T>C	p.Leu125Leu	synonymous	Exon 4 of 8	NP_008940.2
	ZPBP	NM_001159878.2		c.372T>C	p.Leu124Leu	synonymous	Exon 4 of 8	NP_001153350.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZPBP	ENST00000046087.7	TSL:1 MANE Select	c.375T>C	p.Leu125Leu	synonymous	Exon 4 of 8	ENSP00000046087.2
	ZPBP	ENST00000419417.5	TSL:1	c.372T>C	p.Leu124Leu	synonymous	Exon 4 of 8	ENSP00000402071.1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4726 AN: 152198 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0311 AC: 7817 AN: 251210 AF XY: 0.0315

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0441

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0370 AC: 54116 AN: 1461478 Hom.: 1125 Cov.: 32 AF XY: 0.0368 AC XY: 26741 AN XY: 727044

African (AFR) AF: 0.0100 AC: 335 AN: 33460

American (AMR) AF: 0.0195 AC: 873 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 1215 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39646

South Asian (SAS) AF: 0.0123 AC: 1058 AN: 86248

European-Finnish (FIN) AF: 0.0412 AC: 2198 AN: 53396

Middle Eastern (MID) AF: 0.0433 AC: 248 AN: 5734

European-Non Finnish (NFE) AF: 0.0415 AC: 46127 AN: 1111782

Other (OTH) AF: 0.0341 AC: 2061 AN: 60378

GnomAD4 genome AF: 0.0310 AC: 4727 AN: 152316 Hom.: 89 Cov.: 32 AF XY: 0.0297 AC XY: 2212 AN XY: 74480

African (AFR) AF: 0.0115 AC: 477 AN: 41574

American (AMR) AF: 0.0235 AC: 359 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 164 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4822

European-Finnish (FIN) AF: 0.0409 AC: 434 AN: 10620

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3060 AN: 68028

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0393 Hom.: 302

Bravo AF: 0.0295

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0467

EpiControl AF: 0.0493

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ZPBP-related disorder Benign:1

Feb 18, 2020

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.6
DANN	Benign	0.77
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76027725; hg19: chr7-50097697;