rs2293766

Positions:

• chr7-100773735-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_003386.3(ZAN):​c.5649G>A​(p.Trp1883Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0428 in 1,609,900 control chromosomes in the GnomAD database, including 11,702 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.057 (1284 hom., cov: 33)
  • Exomes 𝑓: 0.041 (10418 hom.)
• Consequence: ZAN NM_003386.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90

Genes affected

ZAN (HGNC:12857): (zonadhesin) This gene encodes a protein that functions in the species specificity of sperm adhesion to the egg zona pellucida. The encoded protein is located in the acrosome and may be involved in signaling or gamete recognition. An allelic polymorphism in this gene results in both functional and frameshifted alleles; the reference genome represents the functional allele. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZAN	NM_003386.3	c.5649G>A	p.Trp1883Ter	stop_gained	31/48	ENST00000613979.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAN	ENST00000613979.5	c.5649G>A	p.Trp1883Ter	stop_gained	31/48	1	NM_003386.3	P1

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8640 AN: 152088 Hom.: 1276 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.114 AC: 27608 AN: 241580 Hom.: 5005 AF XY: 0.103 AC XY: 13530 AN XY: 131190

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.0455

Gnomad EAS exome AF: 0.530

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.0390

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.0732

GnomAD4 exome AF: 0.0413 AC: 60195 AN: 1457690 Hom.: 10418 Cov.: 34 AF XY: 0.0424 AC XY: 30759 AN XY: 724778

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.0446

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.00439

Gnomad4 OTH exome AF: 0.0594

GnomAD4 genome AF: 0.0569 AC: 8665 AN: 152210 Hom.: 1284 Cov.: 33 AF XY: 0.0659 AC XY: 4902 AN XY: 74426

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.0388

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.0318 Hom.: 1801

Bravo AF: 0.0695

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0236 AC: 99

ESP6500EA AF: 0.00711 AC: 60

ExAC AF: 0.100 AC: 12110

Asia WGS AF: 0.283 AC: 983 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	4.7e-19	P;P;P;P
Vest4		0.79
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2293766; hg19: chr7-100371358; COSMIC: COSV61807659;