NM_003386.3:c.427C>T

Variant names:

• chr7-100736982-C-T
• rs200501007
• NM_003386.3:c.427C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003386.3(ZAN):​c.427C>T​(p.Arg143Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,502,704 control chromosomes in the GnomAD database, including 49 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (4 hom., cov: 26)
  • Exomes 𝑓: 0.00019 (45 hom.)
• Consequence: ZAN NM_003386.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.594
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009850055).
• 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.427C>T	p.Arg143Cys	missense	Exon 5 of 48	NP_003377.2	Q9Y493-1
	ZAN	NM_173059.3		c.427C>T	p.Arg143Cys	missense	Exon 5 of 46	NP_775082.2	Q9Y493-6
	ZAN	NR_111917.2		n.623C>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.427C>T	p.Arg143Cys	missense	Exon 5 of 48	ENSP00000480750.1	Q9Y493-1
	ZAN	ENST00000620596.4	TSL:1	c.427C>T	p.Arg143Cys	missense	Exon 5 of 46	ENSP00000481742.1	Q9Y493-6
	ZAN	ENST00000538115.5	TSL:1	n.427C>T		non_coding_transcript_exon	Exon 5 of 47	ENSP00000445091.2	Q9Y493-4

Frequencies

GnomAD3 genomes AF: 0.000254 AC: 36 AN: 141622 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.000155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000209

Gnomad ASJ AF: 0.00447

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000190

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000390 AC: 78 AN: 199924 AF XY: 0.000338

Gnomad AFR exome AF: 0.0000910

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.00473

Gnomad EAS exome AF: 0.000126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.000590

GnomAD4 exome AF: 0.000190 AC: 259 AN: 1361082 Hom.: 45 Cov.: 32 AF XY: 0.000175 AC XY: 118 AN XY: 675712

African (AFR) AF: 0.0000626 AC: 2 AN: 31966

American (AMR) AF: 0.000397 AC: 16 AN: 40314

Ashkenazi Jewish (ASJ) AF: 0.00393 AC: 97 AN: 24668

East Asian (EAS) AF: 0.0000785 AC: 3 AN: 38214

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47196

Middle Eastern (MID) AF: 0.000709 AC: 4 AN: 5642

European-Non Finnish (NFE) AF: 0.0000986 AC: 102 AN: 1034892

Other (OTH) AF: 0.000584 AC: 33 AN: 56498

GnomAD4 genome AF: 0.000254 AC: 36 AN: 141622 Hom.: 4 Cov.: 26 AF XY: 0.000203 AC XY: 14 AN XY: 69080

African (AFR) AF: 0.000155 AC: 6 AN: 38828

American (AMR) AF: 0.000209 AC: 3 AN: 14372

Ashkenazi Jewish (ASJ) AF: 0.00447 AC: 15 AN: 3358

East Asian (EAS) AF: 0.00 AC: 0 AN: 4946

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000190 AC: 12 AN: 63022

Other (OTH) AF: 0.00 AC: 0 AN: 1932

Alfa AF: 0.00146 Hom.: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000258 AC: 2

ExAC AF: 0.000289 AC: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.59
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.13
Sift4G	Uncertain	0.012	D
Polyphen		0.96	D
Vest4		0.22
MVP		0.29
MPC		0.42
ClinPred		0.63	D
GERP RS		-2.4
Varity_R		0.099
gMVP		0.80
Mutation Taster		=96/4	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: rs200501007; hg19: chr7-100334605; COSMIC: COSV61814354;