Variant 4-48490349-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_175619.3(ZAR1):c.58T>C(p.Cys20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,513,926 control chromosomes in the GnomAD database, including 1 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 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

ZAR1
NM_175619.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

Variant links:

Genes affected

ZAR1 (HGNC:20436): (zygote arrest 1) This maternal effect gene is oocyte-specific and encodes a protein that is thought to function in the initiation of embryogenesis. A similar protein in mouse is required for female fertility. [provided by RefSeq, Jul 2013]

ZAR1 links:

ZAR1 (HGNC:):

ZAR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006639093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZAR1	NM_175619.3 linkuse as main transcript	c.58T>C	p.Cys20Arg	missense_variant	1/4	ENST00000327939.4	NP_783318.1	Q86SH2B9EG67
ZAR1	XR_007096396.1 linkuse as main transcript	n.98T>C		non_coding_transcript_exon_variant	1/6
ZAR1	XR_925129.4 linkuse as main transcript	n.98T>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZAR1	ENST00000327939.4 linkuse as main transcript	c.58T>C	p.Cys20Arg	missense_variant	1/4	1	NM_175619.3	ENSP00000329803.4		Q86SH2

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00321

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000341

AC:

AN:

114286

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

64072

show subpopulations

Gnomad AFR exome

AF:

0.000376

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00304

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.000306

GnomAD4 exome

AF:

0.000500

AC:

681

AN:

1361864

Hom.:

Cov.:

AF XY:

0.000464

AC XY:

312

AN XY:

672858

show subpopulations

Gnomad4 AFR exome

AF:

0.000108

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00383

Gnomad4 NFE exome

AF:

0.000487

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.000401

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00321

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.000246

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.58T>C (p.C20R) alteration is located in exon 1 (coding exon 1) of the ZAR1 gene. This alteration results from a T to C substitution at nucleotide position 58, causing the cysteine (C) at amino acid position 20 to be replaced by an arginine (R). 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

0.17

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.087

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.87

REVEL

Benign

0.033

Sift

Benign

0.30

Sift4G

Uncertain

0.033

Polyphen

0.0010

Vest4

0.12

MVP

0.030

MPC

1.5

ClinPred

0.0054

GERP RS

-0.55

Varity_R

0.16

gMVP

0.51

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