NM_003386.3:c.430C>T

Variant names:

• chr7-100736985-C-T
• rs201467036
• NM_003386.3:c.430C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003386.3(ZAN):​c.430C>T​(p.Arg144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,502,618 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (4 hom., cov: 26)
  • Exomes 𝑓: 0.00043 (102 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.00
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03756377).
• BP6: Variant 7-100736985-C-T is Benign according to our data. Variant chr7-100736985-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2349642.
• BS2: High Homozygotes in GnomAd4 at 4 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.430C>T	p.Arg144Cys	missense	Exon 5 of 48	NP_003377.2	Q9Y493-1
	ZAN	NM_173059.3		c.430C>T	p.Arg144Cys	missense	Exon 5 of 46	NP_775082.2	Q9Y493-6
	ZAN	NR_111917.2		n.626C>T		non_coding_transcript_exon	Exon 5 of 48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAN	ENST00000613979.5	TSL:1 MANE Select	c.430C>T	p.Arg144Cys	missense	Exon 5 of 48	ENSP00000480750.1	Q9Y493-1
	ZAN	ENST00000620596.4	TSL:1	c.430C>T	p.Arg144Cys	missense	Exon 5 of 46	ENSP00000481742.1	Q9Y493-6
	ZAN	ENST00000538115.5	TSL:1	n.430C>T		non_coding_transcript_exon	Exon 5 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes AF: 0.000254 AC: 36 AN: 141688 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.0000515

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000696

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000428

Gnomad OTH AF: 0.000520

GnomAD2 exomes AF: 0.000535 AC: 107 AN: 199974 AF XY: 0.000448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000101

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000665

Gnomad OTH exome AF: 0.000393

GnomAD4 exome AF: 0.000428 AC: 583 AN: 1360930 Hom.: 102 Cov.: 32 AF XY: 0.000413 AC XY: 279 AN XY: 675556

African (AFR) AF: 0.0000313 AC: 1 AN: 31950

American (AMR) AF: 0.0000745 AC: 3 AN: 40280

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 31 AN: 24662

East Asian (EAS) AF: 0.00128 AC: 49 AN: 38174

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47260

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5640

European-Non Finnish (NFE) AF: 0.000450 AC: 466 AN: 1034792

Other (OTH) AF: 0.000549 AC: 31 AN: 56484

GnomAD4 genome AF: 0.000254 AC: 36 AN: 141688 Hom.: 4 Cov.: 26 AF XY: 0.000217 AC XY: 15 AN XY: 69140

African (AFR) AF: 0.0000515 AC: 2 AN: 38860

American (AMR) AF: 0.0000696 AC: 1 AN: 14360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.00101 AC: 5 AN: 4942

South Asian (SAS) AF: 0.00 AC: 0 AN: 4578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9474

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

European-Non Finnish (NFE) AF: 0.000428 AC: 27 AN: 63056

Other (OTH) AF: 0.000520 AC: 1 AN: 1924

Alfa AF: 0.000634 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000129 AC: 1

ExAC AF: 0.000491 AC: 56

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.0
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.13
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.40
MVP		0.33
MPC		0.46
ClinPred		0.088	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.81
Mutation Taster		=88/12	polymorphism

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: rs201467036; hg19: chr7-100334608; COSMIC: COSV61807322;