Genetic Variant ZIC3:p.Ala51_Ala54dup (chrX-137566825-A-ACGCCGCCGCCGC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_003413.4(ZIC3):c.150_161dupCGCCGCCGCCGC(p.Ala51_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 0.00000517 in 1,160,682 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. Synonymous variant affecting the same amino acid position (i.e. A54A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000038 ( 0 hom. 1 hem. )

Consequence

ZIC3
NM_003413.4 disruptive_inframe_insertion

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 -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003413.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4 link	c.150_161dupCGCCGCCGCCGC	p.Ala51_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1 link	c.150_161dupCGCCGCCGCCGC	p.Ala51_Ala54dup	disruptive_inframe_insertion	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_161dupCGCCGCCGCCGC	p.Ala51_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5	O60481-1
ZIC3	ENST00000370606.3 link	c.150_161dupCGCCGCCGCCGC	p.Ala51_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	5		ENSP00000359638.3	O60481-2
LINC02931	ENST00000786828.1 link	n.130+2237_130+2248dupGCGGCGGCGGCG		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111761

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:

0.000285

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000381

AC:

AN:

1048878

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

341520

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25002

American (AMR)

AF:

0.0000355

AC:

AN:

28191

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18644

East Asian (EAS)

AF:

0.00

AC:

AN:

27323

South Asian (SAS)

AF:

0.0000401

AC:

AN:

49919

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3940

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

820182

Other (OTH)

AF:

0.00

AC:

AN:

44329

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.013624), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111804

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30922

American (AMR)

AF:

0.00

AC:

AN:

10724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.000286

AC:

AN:

3496

South Asian (SAS)

AF:

0.00

AC:

AN:

2687

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52915

Other (OTH)

AF:

0.00

AC:

AN:

1517

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Splicing

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

Publications

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X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over