X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_003413.4(ZIC3):c.159_161dup(p.Ala54dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,160,230 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,071 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., 59 hem., cov: 24)
  • Exomes 𝑓: 0.0043 (9 hom. 1012 hem.)
• Consequence: ZIC3 NM_003413.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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 -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-A-ACGC is Benign according to our data. Variant chrX-137566825-A-ACGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259047.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd at 59 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.159_161dup	p.Ala54dup	inframe_insertion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.159_161dup	p.Ala54dup	inframe_insertion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.159_161dup	p.Ala54dup	inframe_insertion	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.159_161dup	p.Ala54dup	inframe_insertion	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 276 AN: 111757 Hom.: 1 Cov.: 24 AF XY: 0.00173 AC XY: 59 AN XY: 34145

Gnomad AFR AF: 0.000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000560

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00222

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00418

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00205 AC: 198 AN: 96477 Hom.: 2 AF XY: 0.00157 AC XY: 51 AN XY: 32583

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000527

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.000810

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00426 AC: 4468 AN: 1048430 Hom.: 9 Cov.: 33 AF XY: 0.00297 AC XY: 1012 AN XY: 341090

Gnomad4 AFR exome AF: 0.000880

Gnomad4 AMR exome AF: 0.000781

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000293

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00505

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00247 AC: 276 AN: 111800 Hom.: 1 Cov.: 24 AF XY: 0.00173 AC XY: 59 AN XY: 34198

Gnomad4 AFR AF: 0.000970

Gnomad4 AMR AF: 0.000559

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00223

Gnomad4 FIN AF: 0.00117

Gnomad4 NFE AF: 0.00420

Gnomad4 OTH AF: 0.00264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2023

- -

ZIC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2019

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;