X-137566825-ACGCCGCCGCCGCCGC-ACGCCGC

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_003413.4(ZIC3):c.153_161del(p.Ala53_Ala55del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,160,670 control chromosomes in the GnomAD database, including 1 homozygotes. There are 229 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 23 hem., cov: 24)
  • Exomes 𝑓: 0.00066 (1 hom. 206 hem.)
• Consequence: ZIC3 NM_003413.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3 B:2
• 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 Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-ACGCCGCCGC-A is Benign according to our data. Variant chrX-137566825-ACGCCGCCGC-A is described in ClinVar as [Likely_benign]. Clinvar id is 464970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.153_161del	p.Ala53_Ala55del	inframe_deletion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.153_161del	p.Ala53_Ala55del	inframe_deletion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.153_161del	p.Ala53_Ala55del	inframe_deletion	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.153_161del	p.Ala53_Ala55del	inframe_deletion	1/3	5

Frequencies

GnomAD3 genomes AF: 0.000734 AC: 82 AN: 111758 Hom.: 0 Cov.: 24 AF XY: 0.000674 AC XY: 23 AN XY: 34144

Gnomad AFR AF: 0.000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00171

Gnomad SAS AF: 0.000742

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000605

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000829 AC: 80 AN: 96477 Hom.: 0 AF XY: 0.000921 AC XY: 30 AN XY: 32583

Gnomad AFR exome AF: 0.000793

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00330

Gnomad SAS exome AF: 0.000378

Gnomad FIN exome AF: 0.000162

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000664 AC: 696 AN: 1048869 Hom.: 1 AF XY: 0.000603 AC XY: 206 AN XY: 341511

Gnomad4 AFR exome AF: 0.000920

Gnomad4 AMR exome AF: 0.000780

Gnomad4 ASJ exome AF: 0.0000536

Gnomad4 EAS exome AF: 0.00326

Gnomad4 SAS exome AF: 0.000381

Gnomad4 FIN exome AF: 0.000128

Gnomad4 NFE exome AF: 0.000621

Gnomad4 OTH exome AF: 0.000564

GnomAD4 genome AF: 0.000725 AC: 81 AN: 111801 Hom.: 0 Cov.: 24 AF XY: 0.000673 AC XY: 23 AN XY: 34197

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.000933

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00172

Gnomad4 SAS AF: 0.000744

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000605

Gnomad4 OTH AF: 0.00132

Bravo AF: 0.000880

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2020

- -

ZIC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 29, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;