rs531503

Positions:

• chr7-100779460-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003386.3(ZAN):​c.6332T>C​(p.Leu2111Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,604,854 control chromosomes in the GnomAD database, including 104,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (10358 hom., cov: 33)
  • Exomes 𝑓: 0.36 (93852 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.79

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]

ZAN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0390105E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZAN	NM_003386.3	c.6332T>C	p.Leu2111Pro	missense_variant	35/48	ENST00000613979.5	NP_003377.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZAN	ENST00000613979.5	c.6332T>C	p.Leu2111Pro	missense_variant	35/48	1	NM_003386.3	ENSP00000480750.1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55658 AN: 151964 Hom.: 10343 Cov.: 33

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.336

GnomAD3 exomes AF: 0.347 AC: 83404 AN: 240422 Hom.: 14790 AF XY: 0.345 AC XY: 45217 AN XY: 130946

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.324

Gnomad SAS exome AF: 0.283

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.357 AC: 518461 AN: 1452772 Hom.: 93852 Cov.: 47 AF XY: 0.355 AC XY: 256086 AN XY: 721458

Gnomad4 AFR exome AF: 0.399

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.366 AC: 55698 AN: 152082 Hom.: 10358 Cov.: 33 AF XY: 0.364 AC XY: 27082 AN XY: 74350

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.426

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.332

Alfa AF: 0.362 Hom.: 14965

Bravo AF: 0.363

TwinsUK AF: 0.369 AC: 1367

ALSPAC AF: 0.356 AC: 1372

ESP6500AA AF: 0.390 AC: 1603

ESP6500EA AF: 0.361 AC: 3028

ExAC AF: 0.349 AC: 42134

Asia WGS AF: 0.312 AC: 1087 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.13
DANN	Benign	0.15
DEOGEN2	Benign	0.0053	T;.;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.20	.;.;T;T
MetaRNN	Benign	0.00070	T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.29	T
REVEL	Benign	0.010
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.042
MPC		0.11
ClinPred		0.0096	T
GERP RS		-2.4
Varity_R		0.077
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs531503; hg19: chr7-100377082; COSMIC: COSV61810705;