X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGCCGC

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_161del(p.Ala55del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,155,920 control chromosomes in the GnomAD database, including 1 homozygotes. There are 149 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.00033 (1 hom. 141 hem.)
• Consequence: ZIC3 NM_003413.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-ACGC-A is Benign according to our data. Variant chrX-137566825-ACGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573248.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}. Variant chrX-137566825-ACGC-A is described in Lovd as [Likely_benign]. Variant chrX-137566825-ACGC-A is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.159_161del	p.Ala55del	inframe_deletion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.159_161del	p.Ala55del	inframe_deletion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.159_161del	p.Ala55del	inframe_deletion	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.159_161del	p.Ala55del	inframe_deletion	1/3	5

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111747 Hom.: 0 Cov.: 24 AF XY: 0.000205 AC XY: 7 AN XY: 34143

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00104 AC: 100 AN: 96477 Hom.: 0 AF XY: 0.000982 AC XY: 32 AN XY: 32583

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.000348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00469

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000330 AC: 345 AN: 1044131 Hom.: 1 AF XY: 0.000417 AC XY: 141 AN XY: 338231

Gnomad4 AFR exome AF: 0.0000806

Gnomad4 AMR exome AF: 0.0000717

Gnomad4 ASJ exome AF: 0.0000540

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.00513

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.0000404

Gnomad4 OTH exome AF: 0.000295

GnomAD4 genome AF: 0.000152 AC: 17 AN: 111789 Hom.: 0 Cov.: 24 AF XY: 0.000234 AC XY: 8 AN XY: 34195

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00558

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 06, 2018	Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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 poor data quality at this position in the ExAC database. This variant, c.159_161delCGC, results in the deletion of 1 amino acid(s) of the ZIC3 protein (p.Ala55del), but otherwise preserves the integrity of the reading frame. 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

Sep 24, 2019

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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;