NM_207341.4:c.319G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_207341.4(ZP1):c.319G>A(p.Asp107Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,600,752 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 15 hom. )

Consequence

ZP1
NM_207341.4 missense, splice_region

Scores

Splicing: ADA: 0.9251

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.75

Publications

6 publications found

Variant links:

Genes affected

ZP1 (HGNC:13187): (zona pellucida glycoprotein 1) The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by this gene ensures the structural integrity of the zona pellucida. Mutations in this gene are a cause of oocyte maturation defect and infertility. [provided by RefSeq, May 2014]

ZP1 Gene-Disease associations (from GenCC):

female infertility due to zona pellucida defect
Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ZP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063221753).

BP6

Variant 11-60869537-G-A is Benign according to our data. Variant chr11-60869537-G-A is described in ClinVar as Benign. ClinVar VariationId is 2641815.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00196 (298/152254) while in subpopulation AMR AF = 0.0034 (52/15292). AF 95% confidence interval is 0.00266. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZP1	NM_207341.4 link	c.319G>A	p.Asp107Asn	missense_variant, splice_region_variant	Exon 3 of 12	ENST00000278853.10	NP_997224.2	P60852V9HWI9
ZP1	XM_011544853.3 link	c.-198+271G>A		intron_variant	Intron 1 of 9		XP_011543155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZP1	ENST00000278853.10 link	c.319G>A	p.Asp107Asn	missense_variant, splice_region_variant	Exon 3 of 12	1	NM_207341.4	ENSP00000278853.5		P60852
ZP1	ENST00000540908.1 link	n.108+271G>A		intron_variant	Intron 1 of 2	5		ENSP00000441293.1		H0YG11

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

298

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00253

AC:

616

AN:

243100

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00282

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.00322

GnomAD4 exome

AF:

0.00203

AC:

2935

AN:

1448498

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1473

AN XY:

718740

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33306

American (AMR)

AF:

0.00308

AC:

136

AN:

44152

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

515

AN:

25170

East Asian (EAS)

AF:

0.000582

AC:

AN:

39518

South Asian (SAS)

AF:

0.000839

AC:

AN:

84664

European-Finnish (FIN)

AF:

0.0000568

AC:

AN:

52860

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00170

AC:

1874

AN:

1103360

Other (OTH)

AF:

0.00353

AC:

211

AN:

59766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

171

341

512

682

853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00196

AC:

298

AN:

152254

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41534

American (AMR)

AF:

0.00340

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

68016

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00271

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00217

AC:

263

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZP1: BP4, BS1, BS2 -

ZP1-related disorder

Benign:1

May 15, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

Eigen

Benign

-0.030

Eigen_PC

Benign

-0.063

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.60

M_CAP

Benign

0.0084

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

1.8

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

REVEL

Benign

0.083

Sift

Uncertain

0.019

Sift4G

Benign

0.13

Polyphen

0.84

Vest4

0.078

MVP

0.46

MPC

0.20

ClinPred

0.026

GERP RS

4.3

Varity_R

0.073

gMVP

0.52

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over