rs531503

Variant names:

• chr7-100779460-T-C
• rs531503
• NM_003386.3:c.6332T>C

Variant summary

Our verdict is Benign. The variant received -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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003386.3. 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
	ZAN	NM_003386.3	MANE Select	c.6332T>C	p.Leu2111Pro	missense	Exon 35 of 48	NP_003377.2
	ZAN	NM_173059.3		c.6332T>C	p.Leu2111Pro	missense	Exon 35 of 46	NP_775082.2
	ZAN	NR_111917.2		n.6528T>C		non_coding_transcript_exon	Exon 35 of 48

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAN	ENST00000613979.5	TSL:1 MANE Select	c.6332T>C	p.Leu2111Pro	missense	Exon 35 of 48	ENSP00000480750.1
	ZAN	ENST00000620596.4	TSL:1	c.6332T>C	p.Leu2111Pro	missense	Exon 35 of 46	ENSP00000481742.1
	ZAN	ENST00000538115.5	TSL:1	n.6332T>C		non_coding_transcript_exon	Exon 35 of 47	ENSP00000445091.2

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

GnomAD2 exomes AF: 0.347 AC: 83404 AN: 240422 AF XY: 0.345

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 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

African (AFR) AF: 0.399 AC: 13324 AN: 33380

American (AMR) AF: 0.288 AC: 12756 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 11324 AN: 26034

East Asian (EAS) AF: 0.302 AC: 11891 AN: 39438

South Asian (SAS) AF: 0.283 AC: 24265 AN: 85830

European-Finnish (FIN) AF: 0.403 AC: 20541 AN: 50986

Middle Eastern (MID) AF: 0.251 AC: 1441 AN: 5750

European-Non Finnish (NFE) AF: 0.363 AC: 401573 AN: 1107002

Other (OTH) AF: 0.356 AC: 21346 AN: 60040

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

African (AFR) AF: 0.395 AC: 16391 AN: 41512

American (AMR) AF: 0.293 AC: 4474 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1477 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1733 AN: 5156

South Asian (SAS) AF: 0.294 AC: 1418 AN: 4828

European-Finnish (FIN) AF: 0.411 AC: 4344 AN: 10580

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24766 AN: 67968

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.363 Hom.: 22650

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 v4.9

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
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00070	T
MetaSVM	Benign	-0.92	T
PhyloP100		-3.8
PrimateAI	Benign	0.29	T
REVEL	Benign	0.010
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.11
ClinPred		0.0096	T
GERP RS		-2.4
Varity_R		0.077
gMVP		0.73
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs531503; hg19: chr7-100377082; COSMIC: COSV61810705;