Genetic Variant NM_003413.4:c.159_161delCGC (chrX-137566825-ACGC-A) – 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_161delCGC(p.Ala54del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,155,920 control chromosomes in the GnomAD database, including 1 homozygotes. There are 149 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. A53A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 8 hem., cov: 24)

Exomes 𝑓: 0.00033 ( 1 hom. 141 hem. )

Consequence

ZIC3
NM_003413.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

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-ACGC-A is Benign according to our data. Variant chrX-137566825-ACGC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 573248.

BS2

High Hemizygotes in GnomAd4 at 8 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_161delCGC	p.Ala54del	disruptive_inframe_deletion	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.159_161delCGC	p.Ala54del	disruptive_inframe_deletion	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_161delCGC	p.Ala54del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000287538.5	O60481-1
ZIC3	ENST00000919832.1		c.159_161delCGC	p.Ala54del	disruptive_inframe_deletion	Exon 4 of 6	ENSP00000589891.1
ZIC3	ENST00000919833.1		c.159_161delCGC	p.Ala54del	disruptive_inframe_deletion	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111747

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00519

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00104

AC:

100

AN:

96477

AF XY:

0.000982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000216

Gnomad ASJ exome

AF:

0.000348

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.000322

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000330

AC:

345

AN:

1044131

Hom.:

AF XY:

0.000417

AC XY:

141

AN XY:

338231

show subpopulations

African (AFR)

AF:

0.0000806

AC:

AN:

24806

American (AMR)

AF:

0.0000717

AC:

AN:

27901

Ashkenazi Jewish (ASJ)

AF:

0.0000540

AC:

AN:

18504

East Asian (EAS)

AF:

0.000111

AC:

AN:

27108

South Asian (SAS)

AF:

0.00513

AC:

253

AN:

49329

European-Finnish (FIN)

AF:

0.00119

AC:

AN:

31137

Middle Eastern (MID)

AF:

0.000256

AC:

AN:

3909

European-Non Finnish (NFE)

AF:

0.0000404

AC:

AN:

817341

Other (OTH)

AF:

0.000295

AC:

AN:

44096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

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:

0.000152

AC:

AN:

111789

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34195

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30920

American (AMR)

AF:

0.00

AC:

AN:

10722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3496

South Asian (SAS)

AF:

0.00558

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6005

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52909

Other (OTH)

AF:

0.00

AC:

AN:

1516

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

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:

0.00449

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heterotaxy, visceral, 1, X-linked (2)

ZIC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=67/33

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