Genetic Variant ZAN:p.Arg143Cys (chr7-100736982-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 4 hom., cov: 26)

Exomes 𝑓: 0.00019 ( 45 hom. )

Consequence

ZAN
NM_003386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.594

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009850055).

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAN	NM_003386.3 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 5 of 48	ENST00000613979.5	NP_003377.2	Q9Y493-1B4DYT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAN	ENST00000613979.5 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 5 of 48	1	NM_003386.3	ENSP00000480750.1		Q9Y493-1

Frequencies

GnomAD3 genomes

AF:

0.000254

AC:

AN:

141622

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000390

AC:

AN:

199924

Hom.:

AF XY:

0.000338

AC XY:

AN XY:

109332

show subpopulations

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 SAS exome

AF:

0.0000373

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.:

Cov.:

AF XY:

0.000175

AC XY:

118

AN XY:

675712

show subpopulations

Gnomad4 AFR exome

AF:

0.0000626

Gnomad4 AMR exome

AF:

0.000397

Gnomad4 ASJ exome

AF:

0.00393

Gnomad4 EAS exome

AF:

0.0000785

Gnomad4 SAS exome

AF:

0.0000245

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000986

Gnomad4 OTH exome

AF:

0.000584

GnomAD4 genome

AF:

0.000254

AC:

AN:

141622

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

69080

show subpopulations

Gnomad4 AFR

AF:

0.000155

Gnomad4 AMR

AF:

0.000209

Gnomad4 ASJ

AF:

0.00447

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000190

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00146

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000258

AC:

ExAC

AF:

0.000289

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.427C>T (p.R143C) alteration is located in exon 5 (coding exon 4) of the ZAN gene. This alteration results from a C to T substitution at nucleotide position 427, causing the arginine (R) at amino acid position 143 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

T;.;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.48

.;.;T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.0099

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;L;L;L

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.6

.;.;.;D

REVEL

Benign

0.13

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.96

D;.;D;.

Vest4

0.22

MVP

0.29

MPC

0.42

ClinPred

0.63

GERP RS

-2.4

Varity_R

0.099

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over