rs755343529

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003413.4(ZIC3):c.1248T>G(p.Asp416Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,209,503 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 89 hemizygotes in GnomAD. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00013 ( 0 hom. 86 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.95

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

heterotaxy, visceral, 1, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
VACTERL association, X-linked, with or without hydrocephalus
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P

ZIC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017792434).

BP6

Variant X-137569914-T-G is Benign according to our data. Variant chrX-137569914-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533553.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	NM_003413.4	MANE Select	c.1248T>G	p.Asp416Glu	missense	Exon 3 of 3	NP_003404.1
	ZIC3	NM_001330661.1		c.1224+849T>G		intron	N/A	NP_001317590.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.1248T>G	p.Asp416Glu	missense	Exon 3 of 3	ENSP00000287538.5
ZIC3	ENST00000478471.1	TSL:2	n.285T>G		non_coding_transcript_exon	Exon 2 of 2
ZIC3	ENST00000370606.3	TSL:5	c.1224+849T>G		intron	N/A	ENSP00000359638.3

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111595

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000755

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000169

AC:

AN:

183158

AF XY:

0.000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000130

AC:

143

AN:

1097908

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

AN XY:

363266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26397

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00194

AC:

105

AN:

54105

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

841880

Other (OTH)

AF:

0.000174

AC:

AN:

46082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111595

Hom.:

Cov.:

AF XY:

0.0000889

AC XY:

AN XY:

33755

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30657

American (AMR)

AF:

0.00

AC:

AN:

10471

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.000755

AC:

AN:

2650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5987

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53194

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heterotaxy, visceral, 1, X-linked (1)

Inborn genetic diseases (1)

ZIC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.35

M_CAP

Benign

0.034

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.12

REVEL

Benign

0.091

Sift

Benign

0.84

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.038

MutPred

0.29

Gain of glycosylation at S418 (P = 0.1112)

MVP

0.18

MPC

1.2

ClinPred

0.019

GERP RS

6.0

Varity_R

0.21

gMVP

0.33

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over