X-137566740-G-T

Position:

chrX-137566740-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003413.4(ZIC3):c.49G>T(p.Gly17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,190,354 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,091 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., 65 hem., cov: 24)

Exomes 𝑓: 0.0031 ( 7 hom. 1026 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:13

Conservation

PhyloP100: 1.85

Variant links:

Genes affected

ZIC3 (HGNC:12874): (Zic family member 3) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. [provided by RefSeq, Jul 2008]

ZIC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077534616).

BP6

Variant X-137566740-G-T is Benign according to our data. Variant chrX-137566740-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 190129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-137566740-G-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 65 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4 linkuse as main transcript	c.49G>T	p.Gly17Cys	missense_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1 linkuse as main transcript	c.49G>T	p.Gly17Cys	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10 linkuse as main transcript	c.49G>T	p.Gly17Cys	missense_variant	1/3	1	NM_003413.4	P1	O60481-1
ZIC3	ENST00000370606.3 linkuse as main transcript	c.49G>T	p.Gly17Cys	missense_variant	1/3	5			O60481-2

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

227

AN:

113102

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

AN XY:

35250

show subpopulations

Gnomad AFR

AF:

0.000320

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.000830

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00463

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00328

GnomAD3 exomes

AF:

0.00259

AC:

366

AN:

141061

Hom.:

AF XY:

0.00239

AC XY:

103

AN XY:

43075

show subpopulations

Gnomad AFR exome

AF:

0.000408

Gnomad AMR exome

AF:

0.000998

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000128

Gnomad FIN exome

AF:

0.00532

Gnomad NFE exome

AF:

0.00436

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.00311

AC:

3350

AN:

1077197

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

1026

AN XY:

349763

show subpopulations

Gnomad4 AFR exome

AF:

0.000421

Gnomad4 AMR exome

AF:

0.000943

Gnomad4 ASJ exome

AF:

0.00147

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000777

Gnomad4 FIN exome

AF:

0.00515

Gnomad4 NFE exome

AF:

0.00353

Gnomad4 OTH exome

AF:

0.00333

GnomAD4 genome

AF:

0.00201

AC:

227

AN:

113157

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

AN XY:

35315

show subpopulations

Gnomad4 AFR

AF:

0.000320

Gnomad4 AMR

AF:

0.000829

Gnomad4 ASJ

AF:

0.00188

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00463

Gnomad4 NFE

AF:

0.00315

Gnomad4 OTH

AF:

0.00324

Alfa

AF:

0.00297

Hom.:

Bravo

AF:

0.00164

ESP6500AA

AF:

0.00131

AC:

ESP6500EA

AF:

0.00388

AC:

ExAC

AF:

0.00268

AC:

318

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ZIC3: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26294094, 19933292, 24123890, 23427188) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Heterotaxy, visceral, 1, X-linked

Benign:4

Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of X-linked recessive Congenital heart defects, nonsyndromic, 1 (MIM#306955). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

VACTERL association, X-linked, with or without hydrocephalus

Pathogenic:1Benign:1

Pathogenic, flagged submission	research	Reutter Lab, Institute of Human Genetics, University Hospital Bonn	Jan 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1% frequency and 26 hemizygotes in the European population in ExAC -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital heart defects 1, nonsyndromic, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.29

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;.

Vest4

0.48

MVP

0.65

MPC

2.4

ClinPred

0.018

GERP RS

3.3

Varity_R

0.51

gMVP

0.64

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