NM_003386.3:c.68C>T

Variant names:

• chr7-100735734-C-T
• rs746189371
• NM_003386.3:c.68C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003386.3(ZAN):​c.68C>T​(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,508,982 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000016 (3 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.94
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048380077).
• BP6: Variant 7-100735734-C-T is Benign according to our data. Variant chr7-100735734-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2329794.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAN	NM_003386.3	MANE Select	c.68C>T	p.Pro23Leu	missense	Exon 3 of 48	NP_003377.2	Q9Y493-1
	ZAN	NM_173059.3		c.68C>T	p.Pro23Leu	missense	Exon 3 of 46	NP_775082.2	Q9Y493-6
	ZAN	NR_111917.2		n.264C>T		non_coding_transcript_exon	Exon 3 of 48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAN	ENST00000613979.5	TSL:1 MANE Select	c.68C>T	p.Pro23Leu	missense	Exon 3 of 48	ENSP00000480750.1	Q9Y493-1
	ZAN	ENST00000620596.4	TSL:1	c.68C>T	p.Pro23Leu	missense	Exon 3 of 46	ENSP00000481742.1	Q9Y493-6
	ZAN	ENST00000538115.5	TSL:1	n.68C>T		non_coding_transcript_exon	Exon 3 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes AF: 0.0000143 AC: 2 AN: 139848 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000897 AC: 2 AN: 223014 AF XY: 0.0000166

Gnomad AFR exome AF: 0.0000716

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000161 AC: 22 AN: 1369134 Hom.: 3 Cov.: 29 AF XY: 0.0000147 AC XY: 10 AN XY: 680776

African (AFR) AF: 0.0000311 AC: 1 AN: 32140

American (AMR) AF: 0.00 AC: 0 AN: 41268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24852

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38638

South Asian (SAS) AF: 0.00 AC: 0 AN: 83002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48956

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5636

European-Non Finnish (NFE) AF: 0.0000125 AC: 13 AN: 1037830

Other (OTH) AF: 0.000106 AC: 6 AN: 56812

GnomAD4 genome AF: 0.0000143 AC: 2 AN: 139848 Hom.: 0 Cov.: 25 AF XY: 0.0000147 AC XY: 1 AN XY: 68106

African (AFR) AF: 0.0000523 AC: 2 AN: 38228

American (AMR) AF: 0.00 AC: 0 AN: 14042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62634

Other (OTH) AF: 0.00 AC: 0 AN: 1902

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.00000868 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.050
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.9
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.012
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.047
MutPred		0.39		Loss of glycosylation at P23 (P = 0.0054)
MVP		0.18
MPC		0.10
ClinPred		0.037	T
GERP RS		-3.8
Varity_R		0.028
gMVP		0.40
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs746189371; hg19: chr7-100333357;