X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGCCGCCGCCGCCGC

Variant summary

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

The NM_003413.4(ZIC3):c.156_161dup(p.Ala54_Ala55dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,160,528 control chromosomes in the GnomAD database, including 24 homozygotes. There are 490 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (13 hom., 146 hem., cov: 24)
  • Exomes 𝑓: 0.0014 (11 hom. 344 hem.)
• Consequence: ZIC3 NM_003413.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-A-ACGCCGC is Benign according to our data. Variant chrX-137566825-A-ACGCCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411872.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 317 AN: 111751 Hom.: 13 Cov.: 24 AF XY: 0.00428 AC XY: 146 AN XY: 34137

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0453

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000775

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00223 AC: 215 AN: 96477 Hom.: 2 AF XY: 0.00138 AC XY: 45 AN XY: 32583

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000264

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00136 AC: 1423 AN: 1048734 Hom.: 11 Cov.: 33 AF XY: 0.00101 AC XY: 344 AN XY: 341378

Gnomad4 AFR exome AF: 0.0000800

Gnomad4 AMR exome AF: 0.000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000220

Gnomad4 SAS exome AF: 0.0000200

Gnomad4 FIN exome AF: 0.0349

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.000948

GnomAD4 genome AF: 0.00284 AC: 317 AN: 111794 Hom.: 13 Cov.: 24 AF XY: 0.00427 AC XY: 146 AN XY: 34190

Gnomad4 AFR AF: 0.0000970

Gnomad4 AMR AF: 0.0000932

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0453

Gnomad4 NFE AF: 0.000775

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 17, 2022

This variant, c.156_161dup, results in the insertion of 2 amino acid(s) of the ZIC3 protein (p.Ala54_Ala55dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ZIC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 411872). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant 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. -

ZIC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

This variant is classified as 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;