Genetic Variant ZIC3:p.Gly7Arg (chrX-137566710-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PS1_ModeratePM2BP4_Moderate

The NM_003413.4(ZIC3):c.19G>A(p.Gly7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000334 in 1,198,483 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.0000028 ( 0 hom. 0 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.29

Publications

1 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 links:

LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

LINC02931 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PS1

Transcript NM_003413.4 (ZIC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.119133145).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	NM_003413.4	MANE Select	c.19G>A	p.Gly7Arg	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.19G>A	p.Gly7Arg	missense	Exon 1 of 3	NP_001317590.1	O60481-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.19G>A	p.Gly7Arg	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
ZIC3	ENST00000919832.1		c.19G>A	p.Gly7Arg	missense	Exon 4 of 6	ENSP00000589891.1
ZIC3	ENST00000919833.1		c.19G>A	p.Gly7Arg	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

112969

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000652

AC:

AN:

153469

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000911

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1085514

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354396

show subpopulations

African (AFR)

AF:

0.0000763

AC:

AN:

26222

American (AMR)

AF:

0.00

AC:

AN:

34134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19151

East Asian (EAS)

AF:

0.00

AC:

AN:

29743

South Asian (SAS)

AF:

0.00

AC:

AN:

52190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

836915

Other (OTH)

AF:

0.00

AC:

AN:

45625

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000885

AC:

AN:

112969

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35111

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31146

American (AMR)

AF:

0.00

AC:

AN:

10836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6249

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53313

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

ExAC

AF:

0.00000832

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.036

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

4.3

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.58

REVEL

Benign

0.12

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.21

MutPred

0.14

Gain of sheet (P = 0.0101)

MVP

0.16

MPC

2.2

ClinPred

0.39

GERP RS

3.2

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.40

gMVP

0.54

Mutation Taster

=55/45

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

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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

Computational scores

Splicing

Publications

Other links and lift over