X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_003413.4(ZIC3):c.156_161del(p.Ala54_Ala55del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,160,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.000022 (0 hom. 12 hem.)
• Consequence: ZIC3 NM_003413.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.156_161del	p.Ala54_Ala55del	inframe_deletion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.156_161del	p.Ala54_Ala55del	inframe_deletion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.156_161del	p.Ala54_Ala55del	inframe_deletion	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.156_161del	p.Ala54_Ala55del	inframe_deletion	1/3	5

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111761 Hom.: 0 Cov.: 24 AF XY: 0.0000586 AC XY: 2 AN XY: 34147

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000285

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000415 AC: 4 AN: 96477 Hom.: 0 AF XY: 0.0000307 AC XY: 1 AN XY: 32583

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000132

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.0000219 AC: 23 AN: 1048836 Hom.: 0 AF XY: 0.0000351 AC XY: 12 AN XY: 341490

Gnomad4 AFR exome AF: 0.0000800

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000536

Gnomad4 EAS exome AF: 0.0000366

Gnomad4 SAS exome AF: 0.0000200

Gnomad4 FIN exome AF: 0.0000319

Gnomad4 NFE exome AF: 0.0000195

Gnomad4 OTH exome AF: 0.0000226

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111804 Hom.: 0 Cov.: 24 AF XY: 0.0000585 AC XY: 2 AN XY: 34200

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000286

Gnomad4 SAS AF: 0.000372

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2018

This variant has not been reported in the literature in individuals with ZIC3-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant, c.156_161delCGCCGC, results in the deletion of 2 amino acid(s) of the ZIC3 protein (p.Ala54_Ala55del), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs748325646; hg19: chrX-136648984;