Genetic Variant ZIC3:p.Ala51_Ala54del (chrX-137566825-ACGCCGCCGCCGC-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_003413.4(ZIC3):c.150_161delCGCCGCCGCCGC(p.Ala51_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 0.0000681 in 1,160,626 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000067 ( 0 hom. 22 hem. )

Consequence

ZIC3
NM_003413.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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 -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003413.4

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4 link	c.150_161delCGCCGCCGCCGC	p.Ala51_Ala54del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1 link	c.150_161delCGCCGCCGCCGC	p.Ala51_Ala54del	disruptive_inframe_deletion	Exon 1 of 3		NP_001317590.1	O60481-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZIC3	ENST00000287538.10 link	c.150_161delCGCCGCCGCCGC	p.Ala51_Ala54del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5	O60481-1
ZIC3	ENST00000370606.3 link	c.150_161delCGCCGCCGCCGC	p.Ala51_Ala54del	disruptive_inframe_deletion	Exon 1 of 3	5		ENSP00000359638.3	O60481-2
LINC02931	ENST00000786828.1 link	n.130+2237_130+2248delGCGGCGGCGGCG		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000805

AC:

AN:

111760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000934

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000667

AC:

AN:

1048866

Hom.:

AF XY:

0.0000644

AC XY:

AN XY:

341508

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

25002

American (AMR)

AF:

0.000106

AC:

AN:

28190

Ashkenazi Jewish (ASJ)

AF:

0.0000536

AC:

AN:

18643

East Asian (EAS)

AF:

0.00

AC:

AN:

27323

South Asian (SAS)

AF:

0.0000601

AC:

AN:

49918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31346

Middle Eastern (MID)

AF:

0.000254

AC:

AN:

3940

European-Non Finnish (NFE)

AF:

0.0000695

AC:

AN:

820176

Other (OTH)

AF:

0.0000451

AC:

AN:

44328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000805

AC:

AN:

111760

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34146

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30859

American (AMR)

AF:

0.0000934

AC:

AN:

10712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3508

South Asian (SAS)

AF:

0.00

AC:

AN:

2697

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52921

Other (OTH)

AF:

0.00

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000945

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=170/30

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-137566825-ACGCCGCCGCCGC-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over