X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_003413.4(ZIC3):c.153_161dup(p.Ala53_Ala55dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,160,653 control chromosomes in the GnomAD database, including 1 homozygotes. There are 59 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (1 hom. 57 hem.)
• Consequence: ZIC3 NM_003413.4 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B: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 Benign. Variant got -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-A-ACGCCGCCGC is Benign according to our data. Variant chrX-137566825-A-ACGCCGCCGC is described in ClinVar as [Likely_benign]. Clinvar id is 3047546.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.153_161dup	p.Ala53_Ala55dup	inframe_insertion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.153_161dup	p.Ala53_Ala55dup	inframe_insertion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.153_161dup	p.Ala53_Ala55dup	inframe_insertion	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.153_161dup	p.Ala53_Ala55dup	inframe_insertion	1/3	5

Frequencies

GnomAD3 genomes AF: 0.0000984 AC: 11 AN: 111761 Hom.: 0 Cov.: 24 AF XY: 0.0000586 AC XY: 2 AN XY: 34147

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: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000332 AC: 32 AN: 96477 Hom.: 0 AF XY: 0.000491 AC XY: 16 AN XY: 32583

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.0000539

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000134 AC: 141 AN: 1048849 Hom.: 1 Cov.: 33 AF XY: 0.000167 AC XY: 57 AN XY: 341491

Gnomad4 AFR exome AF: 0.000200

Gnomad4 AMR exome AF: 0.0000355

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000183

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000317

Gnomad4 OTH exome AF: 0.000271

GnomAD4 genome AF: 0.0000984 AC: 11 AN: 111804 Hom.: 0 Cov.: 24 AF XY: 0.0000585 AC XY: 2 AN XY: 34200

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.0000932

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000869

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZIC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2023

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;