Genetic Variant ZIC3:p.Ala54dup (chrX-137566825-A-ACGC) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_003413.4(ZIC3):c.159_161dupCGC(p.Ala54dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,160,230 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,071 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A54A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., 59 hem., cov: 24)

Exomes 𝑓: 0.0043 ( 9 hom. 1012 hem. )

Consequence

ZIC3
NM_003413.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.41

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 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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003413.4

BP6

Variant X-137566825-A-ACGC is Benign according to our data. Variant chrX-137566825-A-ACGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259047.

BS2

High Hemizygotes in GnomAd4 at 59 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	NM_003413.4	MANE Select	c.159_161dupCGC	p.Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.159_161dupCGC	p.Ala54dup	disruptive_inframe_insertion	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.159_161dupCGC	p.Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000287538.5	O60481-1
ZIC3	ENST00000919832.1		c.159_161dupCGC	p.Ala54dup	disruptive_inframe_insertion	Exon 4 of 6	ENSP00000589891.1
ZIC3	ENST00000919833.1		c.159_161dupCGC	p.Ala54dup	disruptive_inframe_insertion	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

276

AN:

111757

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000560

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00222

Gnomad FIN

AF:

0.00117

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.00418

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00205

AC:

198

AN:

96477

AF XY:

0.00157

show subpopulations

Gnomad AFR exome

AF:

0.000396

Gnomad AMR exome

AF:

0.000647

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000527

Gnomad FIN exome

AF:

0.000810

Gnomad NFE exome

AF:

0.00408

Gnomad OTH exome

AF:

0.00170

GnomAD4 exome

AF:

0.00426

AC:

4468

AN:

1048430

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

1012

AN XY:

341090

show subpopulations

African (AFR)

AF:

0.000880

AC:

AN:

25000

American (AMR)

AF:

0.000781

AC:

AN:

28187

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18643

East Asian (EAS)

AF:

0.000293

AC:

AN:

27323

South Asian (SAS)

AF:

0.00182

AC:

AN:

49903

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

31247

Middle Eastern (MID)

AF:

0.00203

AC:

AN:

3940

European-Non Finnish (NFE)

AF:

0.00505

AC:

4144

AN:

819869

Other (OTH)

AF:

0.00311

AC:

138

AN:

44318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

245

490

735

980

1225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.00247

AC:

276

AN:

111800

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

AN XY:

34198

show subpopulations

African (AFR)

AF:

0.000970

AC:

AN:

30921

American (AMR)

AF:

0.000559

AC:

AN:

10724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3496

South Asian (SAS)

AF:

0.00223

AC:

AN:

2687

European-Finnish (FIN)

AF:

0.00117

AC:

AN:

6005

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00420

AC:

222

AN:

52915

Other (OTH)

AF:

0.00264

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00124

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

not specified (1)

ZIC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=72/28

polymorphism (auto)

(source)

Splicing

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