rs1556029841

Variant names:

• chrX-137567165-CTACT-C
• rs1556029841
• NM_003413.4:c.476_479delACTT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003413.4(ZIC3):​c.476_479delACTT​(p.Tyr159CysfsTer63) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 25)
• Consequence: ZIC3 NM_003413.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.08
• Publications: 0 publications found

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]

LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-137567165-CTACT-C is Pathogenic according to our data. Variant chrX-137567165-CTACT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 464967.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4	c.476_479delACTT	p.Tyr159CysfsTer63	frameshift_variant	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1	c.476_479delACTT	p.Tyr159CysfsTer63	frameshift_variant	Exon 1 of 3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC3	ENST00000287538.10	c.476_479delACTT	p.Tyr159CysfsTer63	frameshift_variant	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5
ZIC3	ENST00000370606.3	c.476_479delACTT	p.Tyr159CysfsTer63	frameshift_variant	Exon 1 of 3	5		ENSP00000359638.3
LINC02931	ENST00000786828.1	n.130+1905_130+1908delAGTA		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes Cov.: 25

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr159Cysfs*63) in the ZIC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZIC3 are known to be pathogenic (PMID: 24123890). This variant is not present in population databases (gnomAD no frequency). 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: 464967). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556029841; hg19: chrX-136649324;