rs104894963

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003413.4(ZIC3):c.649C>G(p.Pro217Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,210,097 control chromosomes in the GnomAD database, including 14 homozygotes. There are 310 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 0.0060 ( 9 hom., 168 hem., cov: 25)

Exomes 𝑓: 0.00056 ( 5 hom. 142 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: 5.97

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005806178).

BP6

Variant X-137567340-C-G is Benign according to our data. Variant chrX-137567340-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 11439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-137567340-C-G is described in Lovd as [Likely_benign]. Variant chrX-137567340-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.006 (675/112410) while in subpopulation AFR AF= 0.0208 (646/31003). AF 95% confidence interval is 0.0195. There are 9 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4 linkuse as main transcript	c.649C>G	p.Pro217Ala	missense_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1 linkuse as main transcript	c.649C>G	p.Pro217Ala	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10 linkuse as main transcript	c.649C>G	p.Pro217Ala	missense_variant	1/3	1	NM_003413.4	P1	O60481-1
ZIC3	ENST00000370606.3 linkuse as main transcript	c.649C>G	p.Pro217Ala	missense_variant	1/3	5			O60481-2

Frequencies

GnomAD3 genomes

AF:

0.00600

AC:

674

AN:

112356

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

167

AN XY:

34516

show subpopulations

Gnomad AFR

AF:

0.0209

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00151

AC:

272

AN:

180381

Hom.:

AF XY:

0.000838

AC XY:

AN XY:

66845

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.000558

AC:

612

AN:

1097687

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

142

AN XY:

363377

show subpopulations

Gnomad4 AFR exome

AF:

0.0192

Gnomad4 AMR exome

AF:

0.00108

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00600

AC:

675

AN:

112410

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

168

AN XY:

34580

show subpopulations

Gnomad4 AFR

AF:

0.0208

Gnomad4 AMR

AF:

0.00223

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00196

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00680

ESP6500AA

AF:

0.0205

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00156

AC:

189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 22995991, 23427188, 24123890, 14681828, 17764085) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -

Heterotaxy, visceral, 1, X-linked

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Congenital heart defects, multiple types, 1, X-linked

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

VACTERL association, X-linked, with or without hydrocephalus

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign

0.16

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.19

T;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.94

A;A

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.10

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.51

T;T

Polyphen

0.0

B;.

Vest4

0.12

MVP

0.18

MPC

1.2

ClinPred

0.044

GERP RS

3.7

Varity_R

0.10

gMVP

0.30

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